Benzylbenzene derivatives and methods of use

ABSTRACT

Provided are compounds having an inhibitory effect on sodium-dependent glucose cotransporter SGLT. The invention also provides pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions which are affected by SGLT inhibition.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. Ser. No. 13/333,295, filedDec. 21, 2011, which is a continuation of U.S. application Ser. No.12/917,367 (now U.S. Pat. No. 8,106,021), filed Nov. 1, 2010, which is acontinuation of U.S. application Ser. No. 12/197,095 (now U.S. Pat. No.7,838,499), filed Aug. 22, 2008, which claims priority to U.S.Provisional Application No. 60/957,625, filed Aug. 23, 2007, which areincorporated in their entirety herein for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

Not Applicable

BACKGROUND OF THE INVENTION

According to the World Health Organization, approximately 150 millionpeople worldwide have diabetes mellitus. The two principal forms ofdiabetes are type 1 diabetes, in which the pancreas fails to produceinsulin, and type 2 diabetes, in which the body fails to respondproperly to the insulin produced (insulin resistance). Accounting forabout 90% of all diabetes cases, type 2 diabetes is by far the mostcommon. In both types of diabetes, the absence of insulin action orproper response to insulin results in elevated levels of serum glucose(hyperglycemia). Serious complications associated with diabetes includeretinopathy (leading to visual impairment or blindness), cardiovasculardisease, nephropathy, neuropathy, ulcers and diabetic foot disease.

individuals with type 1 diabetes currently require insulin therapy.While in many cases type 2 diabetes can be managed with diet andexercise, drug intervention also frequently is required. Besidesinsulin, which is needed by about one-third of patients with type 2diabetes, current antidiabetic therapies include biguanides (whichdecrease glucose production in the liver and increase sensitivity toinsulin), sulfonylureas and meglitinides (which stimulate insulinproduction), alpha-glucosidase inhibitors (which slow starch absorptionand glucose production), and thiazolidinediones (which increase insulinsensitivity). These medicines are often used in combination, and eventhen may not provide adequate glycemic control or may produce undesiredside effects. Such side effects include lactic acidosis (biguanides),hypoglycemia (sulfonylureas), and edema and weight gain(thiazolidinediones). Therefore, new antidiabetic agents providingimproved glycemic control and lacking these adverse effects are highlydesired.

One promising target for therapeutic intervention in diabetes andrelated disorders is the glucose transport system of the kidneys.Cellular glucose transport is conducted by either facilitative(“passive”) glucose transporters (GLUTs) or sodium-dependent (“active”)glucose cotransporters (SGLTs), SGLT1 is found predominantly in theintestinal brush border, while SGLT2 is localized in the renal proximaltubule and is reportedly responsible for the majority of glucosereuptake by the kidneys. Recent studies suggest that inhibition of renalSGLT may be a useful approach to treating hyperglycemia by increasingthe amount of glucose excreted in the urine (Arakawa K, et al., Br JPharmacol 132:578-86, 2001; Oku A, et al., Diabetes 48:1794-1800, 1999).The potential of this therapeutic approach is further supported byrecent findings that mutations in the SGLT2 gene occur in cases offamilial renal glucosuria, an apparently benign syndrome characterizedby urinary glucose excretion in the presence of normal serum glucoselevels and the absence of general renal dysfunction or other disease(Santer R, et al., J Am Soc Nephrol 14:2873-82, 2003). Therefore,compounds which inhibit SGLT, particularly SGLT2, are promisingcandidates for use as antidiabetic drugs. Compounds previously describedas useful for inhibiting SGLT include C-glycoside derivatives (such asthose described in U.S. Pat. No. 6,414,126, US20040138439,US20050209166, US20050233988, WO2005085237, U.S. Pat. No. 7,094,763,US20060009400, US20060019948, US20060035841, US20060122126,US20060234953, WO2006108842, US20070049537 and WO2007136116),O-glycoside derivatives (such as those described in U.S. Pat. No.6,683,056, US20050187168, US20060166899, US20060234954, US20060247179and US20070185197), spiroketal-glycoside derivatives (described inWO2006080421), cyclohexane derivatives (such as those described inWO2006011469), and thio-glucopyranoside derivatives (such as thosedescribed in US20050209309 and WO2006073197).

BRIEF SUMMARY OF THE INVENTION

The present invention provides compounds having an inhibitory effect onsodium-dependent glucose cotransporter SGLT. The invention also providespharmaceutical compositions, methods of preparing the compounds,synthetic intermediates, and methods of using the compounds,independently or in combination with other therapeutic agents, fortreating diseases and conditions which are affected by SGLT inhibition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the general synthesis method of Scheme I for the preparationof compounds of the invention.

FIG. 2 is the general synthesis method of Scheme II for the preparationof compounds of the invention.

FIG. 3 is the general synthesis method of Scheme III for the preparationof compounds of the invention.

FIG. 4 is the outline for the preparation of intermediate D.

FIG. 5 is the outline for the synthesis of compounds E and F of theinvention.

FIG. 6 is the outline for the synthesis of compound G of the invention.

FIG. 7 is the outline for the synthesis of compounds K and L of theinvention.

FIG. 8 is the outline for the synthesis of compounds M and N of theinvention.

FIG. 9 is the outline for the synthesis of compounds P and Q of theinvention.

FIG. 10 is the outline for the synthesis of compounds R and S of theinvention.

FIG. 11 is the outline for the synthesis of compound T of the invention.

FIG. 12 is the outline for the synthesis of compound V of the invention.

FIG. 13 is the outline for the synthesis of compound W of the invention.

FIG. 14 is the outline for the synthesis of compounds X and Y of theinvention.

FIG. 15 is the outline for the synthesis of compounds Z and AA of theinvention.

FIG. 16 is the outline for the synthesis of compound AD of theinvention.

FIG. 17 is the outline for the synthesis of compound AF of theinvention.

FIG. 18 is the outline for the synthesis of compound AS of theinvention.

FIG. 19 is the outline for the synthesis of compounds AV and AW of theinvention.

FIG. 20 is the outline for the synthesis of compound BE of theinvention.

FIG. 21 is the outline for the synthesis of compound BN of theinvention.

FIG. 22 is the outline for the synthesis of compound CC of theinvention.

FIG. 23 is the outline for the synthesis of compound CF of theinvention.

FIG. 24 is the outline for the synthesis of compound CH of theinvention.

FIG. 25 is the outline for the synthesis of compound CK of theinvention.

FIG. 26 is the outline for the synthesis of compound CP of theinvention.

FIG. 27 is the outline for the synthesis of compound CT of theinvention.

FIG. 28 is the outline for the synthesis of compound CX of theinvention.

FIG. 29 is the outline for the synthesis of compound DJ of theinvention.

FIG. 30 is the outline for the synthesis of complex DM of the invention.

FIG. 31 is the X-ray powder diffraction pattern of complex DM of theinvention.

FIG. 32 is the differential scanning calorimetry spectrum of complex DMof the invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the term “halo” means a monovalent halogen radical oratom selected from Nom, chloro, bromo and iodo. Preferred halo groupsare fluoro, ehloro and bromo.

As used herein, the term “suitable substituent” means a chemically andpharmaceutically acceptable group, i.e., a moiety that does notsignificantly interfere with the preparation of or negate the efficacyof the inventive compounds. Such suitable substituents may be routinelychosen by those skilled in the art. Suitable substituents may beselected from the group consisting of halo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkynyl, C₃-C₈cycloalkenyl, (C₃-C₈ cycloalkyl)C₁-C₆ alkyl, (C₃-C₈ cycloalkyl)C₂-C₆alkenyl, (C₃-C₈ cycloalkyl)C₁-C₆ alkoxy, C₃-C₇ heterocycloalkyl, C₃-C₇heterocycloalkyl)C₁-C₆ alkyl, (C₃-C₇ heterocycloalkyl)C₂-C₆ alkenyl,(C₃-C₇ heterocycloalkyl)C₁-C₆ alkoxy, hydroxy, carboxy, oxo, sulfanyl,C₁-C₆ alkylsulfanyl, aryl, heteroaryl, aryloxy, heteroaryloxy, aralkyl,heteroaralkyl, aralkoxy, heteroaralkoxy, nitro, cyano, amino, C₁-C₆alkylamino, di-(C₁-C₆ alkyl)amino, carbamoyl, (C₁-C₆ alkyl)carbonyl,(C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl, di-(C₁-C₆alkyl)aminocarbonyl, arylcarbonyl, aryloxycarbonyl, (C₁-C₆alkyl)sulfonyl, and arylsulfonyl. The groups listed above as suitablesubstituents are as defined hereinafter except that a suitablesubstituent may not be further optionally substituted.

As used herein, unless otherwise indicated, the term “alkyl” alone or incombination refers to a monovalent saturated aliphatic hydrocarbonradical having the indicated number of carbon atoms. The radical may bea linear or branched chain and, where specified, optionally substitutedwith one to three suitable substituents as defined above. Illustrativeexamples of alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl,amyl, sec-butyl, tert-butyl, tert-pentyl, n-heptyl, n-octyl, n-nonyl,n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyland the like. Preferred alkyl groups include methyl, ethyl, n-propyl andisopropyl. Preferred optional suitable substituents include halo,methoxy, ethoxy, cyano, nitro and amino.

As used herein, unless otherwise indicated, the term “alkenyl” alone orin combination refers to a monovalent aliphatic hydrocarbon radicalhaving the indicated number of carbon atoms and at least onecarbon-carbon double bond. The radical may be a linear or branchedchain, in the E or Z form, and where specified, optionally substitutedwith one to three suitable substituents as defined above. Illustrativeexamples of alkenyl groups include, but are not limited to, vinyl,1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl,2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 4-methyl-2-pentenyl,1,3-pentadienyl, 2,4-pentadienyl, 1,3-butadienyl and the like. Preferredalkenyl groups include vinyl, 1-propenyl and 2-propenyl. Preferredoptional suitable substituents include halo, methoxy, ethoxy, cyano,nitro and amino.

As used herein, unless otherwise indicated, the term “alkynyl” alone orin combination refers to a monovalent aliphatic hydrocarbon radicalhaving the indicated number of carbon atoms and at least onecarbon-carbon triple bond. The radical may be a linear or branched chainand, where specified, optionally substituted with one to three suitablesubstituents as defined above. Illustrative examples of alkynyl groupsinclude, but are not limited to, ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-pentynyl,3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl and the like. Preferredalkynyl groups include ethynyl, 1-propynyl and 2-propynyl. Preferredoptional suitable substituents include halo, methoxy, ethoxy, cyano,nitro and amino.

As used herein, unless otherwise indicated, the term “cycloalkyl” aloneor in combination refers to a monovalent alicyclic saturated hydrocarbonradical having three or more carbons forming a carbocyclic ring and,where specified, optionally substituted with one to three suitablesubstituents defined above. Illustrative examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like. Preferredoptional suitable substituents include halo, methyl, ethyl, methoxy,ethoxy, cyano, nitro and amino.

As used herein, unless otherwise indicated, the term “cycloalkenyl”alone or in combination refers to a monovalent alicyclic hydrocarbonradical having three or more carbons forming a carbocyclic ring and atleast one carbon-carbon double bond and, where specified, optionallysubstituted with one to three suitable substituents as defined above.

Illustrative examples of cycloalkenyl groups include, but are notlimited to, cyclopentenyl, cyclohexenyl and the like. Preferred optionalsuitable substituents include halo, methyl, ethyl, methoxy, ethoxy,cyano, nitro and amino.

As used herein, unless otherwise indicated, the terms“alkylene”,“alkenylene”, “cycloalkylene” and “cycloalkenylene” refer to a divalenthydrocarbon radical that is formed by removal of a hydrogen atom from analkyl, alkenyl, cycloalkyl or cycloalkenyl radical, respectively, assuch terms are defined above.

As used herein, the term “(C₃-C₁₀ cycloalkylene)(C₁-C₆ alkylene)” refersto a divalent hydrocarbon radical that is formed by bonding a C₃-C₁₀cycloalkylene radical with C₁-C₆ alkylene radical, as such terms aredefined above.

As used herein, unless otherwise indicated, the term “aryl” alone or incombination refers to a monovalent aromatic hydrocarbon radical havingsix to ten carbon atoms forming a carbocyclic ring and, where specified,optionally substituted with one to three suitable substituents asdefined above. Illustrative examples of aryl groups include, but are notlimited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like.Preferred aryl groups are phenyl and naphthyl, optionally mono- ordisubstituted by identical or different suitable substituents selectedfrom halo, cyano, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, difluoromethyl,trifluoromethyl, C₁-C₃ alkoxy, difluoromethoxy and trifluoromethoxy.

As used herein, unless otherwise indicated, the term “heterocycloalkyl”alone or in combination refers to a cycloalkyl group as defined above inwhich one or more carbons in the ring is replaced by a heteroatomselected from N, S and O. Illustrative examples of heterocycloalkylgroups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl,piperazinyl, tetrahydropyranyl, and the like.

As used herein, unless otherwise indicated, the term “heteroaryl” aloneor in combination refers to a monovalent aromatic heterocyclic radicalhaving two to nine carbons and one to four heteroatoms selected from N,S and O forming a five- to ten-membered monocyclic or fused bicyclicring and, where specified, optionally substituted with one to threesuitable substituents as defined above. Illustrative examples ofheteroaryl groups include, but are not limited to, pyridyl, pyridazinyl,pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl,quinoxalinyl, quinazolinyl, benzotriazinyl, benzimidazolyl,benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl,isoindolyl, indolizinyl, thienopyridinyl, thienopyrimidinyl,pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl,benzothienyl, isothiazolyl, pyrazolyl, indazolyl, imidazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl,thiazolyl, furyl, thienyl and the like. Five- or six-membered monocyclicheteroaryl rings include: pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl,triazinyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl,furyl, thienyl and the like. Eight- to ten-membered bicyclic heteroarylrings having one to four heteroatoms include: quinolinyl, isoquinolinyl,quinoxalinyl, quinazolinyl, benzotriazinyl, benzimidazolyl,benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl,isoindolyl, indolizinyl, thienopyridinyl, thienopyrimidinyl,pyrazolopyrimidinyl, imidazopyridinyl, benzothiaxolyl, benzofuranyl,benzothienyl, indolyl, indazolyl, and the like. Preferred optionalsuitable substitutions include one or two identical or differentsubstituents selected from halo, cyano, C₁-C₃ alkyl, C₃-C₆ cycloalkyl,difluoromethyl, trifluoromethyl, C₁-C₃ alkoxy, difluoromethoxy andtrifluoromethoxy.

As used herein, unless otherwise indicated, the terms “alkoxy” and“alkyloxy” alone or in combination refer to an aliphatic radical of theform alkyl-O—, wherein alkyl is as defined above, illustrative examplesof alkoxy groups include, but are not limited to, methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy,isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy,octoxy and the like. Preferred alkoxy groups include methoxy and ethoxy.

As used herein, unless otherwise indicated the term “haloalkyl” refersto an alkyl radical as described above substituted with one or morehalogens. Illustrative examples of haloalkyl groups include, but are notlimited to, chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 2,2,2-trichloroethyl and the like.

As used herein, unless otherwise indicated, the term “haloalkoxy” refersto an alkoxy radical as described above substituted with one or morehalogens. Illustrative examples of haloalkoxy groups include, but arenot limited to, trifluoromethoxy, difluoromethoxy and the like.

As used herein, unless otherwise indicated, the term “aralkyl” refers toan alkyl radical of one to six carbons as described above substitutedwith an aryl group as described above.

As used herein, unless otherwise indicated, the term “heteroaralkyl”refers to an alkyl radical of one to six carbons as described abovesubstituted with a heteroaryl group as described above.

As used herein, unless otherwise indicated, the term “aralkoxy” refersto an alkoxy radical of one to six carbons as described abovesubstituted with an aryl group as described above.

As used herein, unless otherwise indicated, the term “heteroaralkoxy”refers to an alkoxy radical of one to six carbons as described abovesubstituted with a heteroaryl group as described above.

As used herein, unless otherwise indicated, the term “carbamoyl” refersto a monovalent radical of the form —C(O)NH(R), wherein R is hydrogen,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, or aryl as such terms aredefined above.

As used herein, unless otherwise indicated, the terms “di-(C₁-C₃alkyl)amino” and “di-(C₁-C₆ alkyl)amino” alone or in combination referto an amino group that is substituted with two groups independentlyselected from C₁-C₃ alkyl or C₁-C₆ alkyl, respectively.

As used herein, the terms “treating” and “treatment” refer to delayingthe onset of, retarding or reversing the progress of or alleviating orpreventing either the disease or condition to which the term applies, orone or more symptoms of such disease or condition.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,intraperitoneal, intramuscular, intralesional, intranasal orsubcutaneous administration, or the implantation of a slow-releasedevice, e.g., a mini-osmotic pump, to a subject. Administration is byany route including parenteral, and transmucosal (e.g., oral, nasal,vaginal, rectal, or transdermal). Parenteral administration includes,e.g., intravenous, intramuscular, intra-arteriole, intradermal,subcutaneous, intraperitoneal, intraventricular, and intracranial. Othermodes of delivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, and the like.

As used herein, the term “prodrug” refers to a precursor compound that,following administration, releases the biologically active compound invivo via some chemical or physiological process (e.g., a prodrug onreaching physiological pH or through enzyme action is converted to thebiologically active compound). A prodrug itself may either lack orpossess the desired biological activity.

As used herein, the term “compound” refers to a molecule produced by anymeans including, without limitation, synthesis in vitro or generation insitu or in vivo.

The terms “controlled release,” “sustained release,” “extended release,”and “timed release” are intended to refer interchangeably to anydrug-containing formulation in which release of the drug is notimmediate, i.e., with a “controlled release” formulation, oraladministration does not result in immediate release of the drug into anabsorption pool, terms are used interchangeably with “nonimmediaterelease” as defined in Remington: The Science and Practice of Pharmacy,21^(st) Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2003). Asdiscussed therein, immediate and nonimmediate release can be definedkinetically by reference to the following equation:

The “absorption pool” represents a solution of the drug administered ata particular absorption site, and k_(r), k_(a) and k_(e) are first-orderrate constants for (1) release of the drug from the formulation, (2)absorption, and (3) elimination, respectively. For immediate releasedosage forms, the rate constant for drug release k_(r) is far greaterthan the absorption rate constant k_(a). For controlled releaseformulations, the opposite is true, i.e., k_(r)<<k_(a), such that therate of release of drug from the dosage form is the rate-limiting stepin the delivery of the drug to the target area.

The terms “sustained release” and “extended release” are used in theirconventional sense to refer to a drug formulation that provides forgradual release of a drug over an extended period of time, for example,12 hours or more, and that preferably, although not necessarily, resultsin substantially constant blood levels of a drug over an extended timeperiod.

As used herein, the term “delayed release” refers to a pharmaceuticalpreparation that passes through the stomach intact and dissolves in thesmall intestine.

General

The present invention provides compounds having an inhibitory effect onsodium-dependent glucose cotransporter SGLT, preferably SGLT2. Somecompounds according to the present invention also have an inhibitoryeffect on sodium-dependent glucose cotransporter SGLT1. Owing to theirability to inhibit SGLT, the compounds of the present invention aresuitable for the treatment and/or prevention of any and all conditionsand diseases that are affected by inhibition of SGLT activity,particularly SGLT2 activity. Therefore, the compounds of the presentinvention are suitable for the prevention and treatment of diseases andconditions, particularly metabolic disorders, including but not limitedto type 1 and type 2 diabetes mellitus, hyperglycemia, diabeticcomplications (such as retinopathy, nephropathy [e.g., progressive renaldisease], neuropathy, ulcers, micro- and macroangiopathies, and diabeticfoot disease), insulin resistance, metabolic syndrome (Syndrome X),hyperinsulinemia, hypertension, hyperuricemia, obesity, edema,dyslipidemia, chronic heart failure, atherosclerosis and relateddiseases.

The present invention also provides pharmaceutically acceptable saltsand prodrugs of compounds according to the present invention.

The present invention further provides pharmaceutical compositionscomprising an effective amount of a compound or mixture of compoundsaccording to the present invention, or a pharmaceutically acceptablesalt or prodrug thereof, in a pharmaceutically acceptable carrier.

The present invention further provides synthetic intermediates andprocesses for preparing the compounds of the present invention.

The present invention also provides methods of using the compoundsaccording to the present invention, independently or in combination withother therapeutic agents, for treating diseases and conditions which maybe affected by SGLT inhibition.

The present invention also provides methods of using the compoundsaccording to the present invention for the preparation of a medicamentfor treating diseases and conditions which may be affected by SGLTinhibition.

DETAILED EMBODIMENTS Compounds and Preparative Methods

In one aspect, the present invention provides for compounds of FormulaI:

wherein

V represents oxygen; sulfur; SO; SO₂; or a single bond;

W represents C₁-C₆ alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, C₃-C₁₀cycloalkylene, C₅-C₁₀ cycloalkenylene, or (C₃-C₁₀ cycloalkylene)(C₁-C₆alkylene) where the C₃-C₁₀ cycloalkylene portion bonds to V and theC₁-C₆ alkylene portion bonds to X, and

wherein alkylene, alkenylene, alkynylene, cycloalkylene andcycloalkenylene groups or portions optionally may be partly orcompletely fluorinated and may be mono- or disubstituted by identical ordifferent substituents selected from chlorine, hydroxy, C₁-C₃ alkyl,C₁-C₃ alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyloxy, C₅-C₁₀ cycloalkenylor C₅-C₁₀ cycloalkenyloxy, andin cycloalkylene and cycloalkenylene groups or portions one or twomethylene groups are optionally replaced independently of one another byO, S, CO, SO, SO₂ or NR^(b), and one or two methyne groups areoptionally replaced by N;

X represents oxygen; sulfur; SO; or SO₂;

Y represents hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₁₀ cycloalkenyl,(C₃-C₁₀ cycloalkyl)C₁-C₄ alkyl, (C₅-C₁₀ cycloalkenyl)C₁-C₃ (C₃-C₁₀cycloalkyl)C₂-C₄ alkenyl, C₃-C₆ cycloalkylidenmethyl, (C₅-C₁₀cycloalkenyl)C₂-C₄ alkenyl, (C₁-C₄ alkyloxy)C₁-C₃ alkyl, (C₂-C₄alkenyloxy)C₁-C₃ alkyl, (C₃-C₁₀ cycloalkyloxy)C₁-C₃ alkyl, (C₅-C₁₀cycloalkenyloxy)C₁-C₃ alkyl, (amino)C₁-C₃ alkyl, (C₁-C₄ alkylamino)C₁-C₃alkyl, di-(C₁-C₃ alkylamino)C₁-C₃ alkyl, (C₁-C₆alkyl)carbonyl(C₁-C₃)alkyl, (C₂-C₆ alkenyl)carbonyl(C₁-C₃)alkyl, (C₂-C₆alkynyl)carbonyl(C₁-C₃)alkyl, (arylcarbonyl)C₁-C₃ alkyl,(heteroarylcarbonyl)C₁-C₃ alkyl, (C₁-C₆ alkylsulfonyl)C₁-C₃ alkyl,(C₂-C₆ alkenylsulfonyl)C₁-C₃ alkyl, (C₂-C₆ alkynylsulfonyl)C₁-C₃ alkyl,(arylsulfonyl)C₁-C₃ (heteroarylsulfonyl)C₁-C₃ alkyl, (C₁-C₆alkyl)aminocarbonyl(C₁-C₃)alkyl, (C₂-C₆alkenyl)aminocarbonyl(C₁-C₃)alkyl, (C₂-C₆alkynyl)aminocarbonyl(C₁-C₃)alkyl, (arylaminocarbonyl)C₁-C₃(heteroarylaminocarbonyl)C₁-C₃ (C₁-C₆ alkyl)carbonyl, (C₂-C₆alkenyl)carbonyl, (C₂-C₆ alkynyl)carbonyl, arylcarbonyl,heteroarylcarbonyl, (C₁-C₆ alkyl)sulfonyl, (C₂-C₆ alkenyl)sulfonyl,(C₂-C₆ alkynyl)sulfonyl, arylsulfonyl or heteroarylsulfonyl;

wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups orportions optionally may be partly or completely fluorinated and may bemono- or disubstituted by identical or different substituents selectedfrom chlorine, hydroxy, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₃-C₆ cycloalkyl,C₃-C₆ cycloalkyloxy, C₅-C₁₀ cycloalkenyl, C₅-C₁₀ cycloalkenyloxy, andNR^(b)R^(c), andin cycloalkyl and cycloalkenyl groups or portions one or two methylenegroups are optionally replaced independently of one another by O, S, CO,SO, SO₂ or NR^(b), and one or two methyne groups are optionally replacedby N, wherein the heterocycle formed by said optional replacement isother than heteroaryl, andwherein when V represents oxygen, sulfur or a single bond and Wrepresents C₁-C₆ alkylene, then Y is other than hydrogen, C₁-C₆ alkyl or(C₃-C₁₀ cycloalkyl)C₁-C₄ alkyl, andwhen V represents oxygen, W represents C₃-C₁₀ cycloalkylene and Xrepresents oxygen, then Y is other than hydrogen, C₁-C₆ alkyl, ortrifluoromethyl, andwhen V represents a single bond and W represents C₂-C₆ alkenylene, C₂-C₆alkynylene, C₃-C₁₀ cycloalkylene or C₅-C₁₀ cycloalkenylene, then Y isother than hydrogen, C₁-C₆ alkyl or (C₃-C₁₀ cycloalkyl)C₁-C₄ alkyl;

and when V represents oxygen, sulfur, SO or SO₂, W represents C₂-C₆alkenylene or C₂-C₆ alkynylene, and Y represents C₃-C₁₀ cycloalkyl orC₅-C₁₀ cycloalkenyl, then X may also represent a single bond;

or X represents NR^(a) and Y represents C₁-C₆ alkylsulfonyl, C₂-C₆alkenylsulfonyl, C₂-C₆ alkynylsulfonyl, arylsulfonyl,heteroarylsulfonyl, C₁-C₆ alkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, (C₁-C₆ alkyl)carbonyl, (C₂-C₆ alkenyl)carbonyl,(C₂-C₆ alkynyl)carbonyl, arylcarbonyl, heteroarylcarbonyl, (C₁-C₆alkyl)aminocarbonyl, (C₂-C₆ alkenyl)aminocarbonyl, (C₂-C₆alkynyl)aminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,(C₁-C₆ alkylsulfonyl)C₁-C₃ alkyl, (C₂-C₆ alkenylsulfonyl)C₁-C₃ alkyl,(C₂-C₆ alkynylsulfonyl)C₁-C₃ alkyl, (arylsulfonyl)C₁-C₃ alkyl,(heteroarylsulfonyl)C₁-C₃ alkyl, (C₁-C₆ alkylsulfinyl)C₁-C₃ alkyl,(arylsulfinyl)C₁-C₃ alkyl, (heteroarylsulfinyl)C₁-C₃ alkyl, (C₁-C₆alkyl)aminocarbonyl(C₁-C₃)alkyl, (C₂-C₆alkenyl)aminocarbonyl(C₁-C₃)alkyl, (C₂-C₆alkynyl)aminocarbonyl(C₁-C₃)alkyl, (arylaminocarbonyl)C₁-C₃ alkyl or(heteroarylaminocarbonyl)C₁-C₃ alkyl;

wherein alkyl, alkenyl and alkynyl portions may be partly or completelyfluorinated, andwhen R^(a) represents H or (C₁-C₄ alkyl)carbonyl, then Y is other than(C₁-C₆ alkyl)carbonyl or arylcarbonyl;

Z represents oxygen; sulfur; SO; SO₂; 1,1-cyclopropylene; carbonyl; ormethylene optionally substituted with one to two substituentsindependently selected from halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₃-C₆ cycloalkyl and C₃-C₆ cycloalkyloxy;

R¹, R² and R³ each independently represent hydrogen, halo, hydroxy,C₁-C₆ alkyl, C₃-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₁₀cycloalkenyl, C₁-C₆ alkyloxy, C₃-C₁₀ cycloalkyloxy, cyano or nitro,wherein alkyl and cycloalkyl groups or portions optionally may bemono-polysubstituted by fluorine, or

in the event that R¹ and R² are bound to two adjacent C atoms of thephenyl ring, R¹ and R² may be joined together such that R¹ and R²together form a C₃-C₅ alkylene, C₃-C₅ alkenylene or butadienylenebridge, which may be partly or completely fluorinated and may be mono-or disubstituted by identical or different substituents selected fromchlorine, hydroxy, C₁-C₃ alkoxy and C₁-C₃ alkyl, and wherein one or twomethylene groups are optionally replaced independently of one another byO, S, CO, SO, SO₂ or NR^(b), and wherein one or two methyne groupsoptionally may be replaced by N;

R⁴ and R⁵ each independently represent hydrogen, halo, cyano, nitro,hydroxy, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₃ alkyloxy or C₃-C₁₀cycloalkyloxy, wherein alkyl and cycloalkyl groups or portionsoptionally may be mono- or polysubstituted by fluorine, or

if R⁴ and R⁵ are bound to two adjacent C atoms of the phenyl ring, R⁴and R⁵ optionally may be joined together such that R⁴ and R⁵ togetherform a C₃-C₅ alkylene, C₃-C₅ alkenylene or butadienylene bridge, whichmay be partly or completely fluorinated and mono- or disubstituted byidentical or different substituents selected from chlorine, hydroxy,C₁-C₃ alkoxy and C₁-C₃ alkyl, and wherein one or two methylene groupsare optionally replaced independently of one another by O, S, CO, SO,SO₂ or NR^(b), and wherein one or two methyne groups may be replaced byN;

R⁶, R⁷, R⁸ and R⁹ each independently represent hydroxy,alkyl)carbonyloxy, (C₁-C₁₈ alkyl)oxycarbonyloxy, arylcarbonyloxy,aryl-(C₁-C₃ alkyl)carbonyloxy, (C₃-C₁₀ cycloalkyl)carbonyloxy, hydrogen,halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,(C₃-C₁₀)cycloalkyl-(C₁-C₃)alkyl, (C₅-C₇)cycloalkenyl-(C₁-C₃)alkyl,aryl-(C₁-C₃)alkyl, heteroaryl-(C₁-C₃)alkyl, C₁-C₆ alkyloxy, C₂-C₆alkenyloxy, C₂-C₆ alkynyloxy, C₃-C₇ cycloalkyloxy, C₅-C₇cycloalkenyloxy, aryloxy, heteroaryloxy,(C₃-C₇)cycloalkyl-(C₁-C₃)alkyloxy, (C₅-C₇)cycloalkenyl-(C₁-C₃)alkyloxy,aryl-(C₁-C₃)alkyloxy, heteroaryl-(C₁-C₃)alkyloxy, aminocarbonyl,hydroxycarbonyl, (C₁-C₄ alkyl)aminocarbonyl, di-(C₁-C₃alkyl)aminocarbonyl, (C₁-C₄ alkyloxy)carbonyl,aminocarbonyl-(C₁-C₃)alkyl, (C₁-C₄ alkyl)aminocarbonyl-(C₁-C₃)alkyl,di-(C₁-C₃ alkyl)aminocarbonyl-(C₁-C₃)alkyl,hydroxycarbonyl-(C₁-C₃)alkyl, (C₁-C₄ alkyloxy)carbonyl-(C₁-C₃)alkyl,(C₃-C₇)cycloalkyloxy-(C₁-C₃)alkyl, (C₅-C₇)cycloalkenyloxy-(C₁-C₃)alkyl,aryloxy-(C₁-C₃)alkyl, heteroaryloxy-(C₁-C₃)alkyl, C₁-C₄alkylsulfonyloxy, arylsulfonyloxy, aryl-(C₁-C₃)alkylsulfonyloxy,trimethylsilyloxy, i-butyldimethylsilyloxy, or cyano;

wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups orportions optionally may be partly or completely fluorinated and may bemono- or disubstituted by identical or different substituents selectedfrom chlorine, hydroxy, C₁-C₃ alkoxy and C₁-C₃ alkyl, andin cycloalkyl and cycloalkenyl groups or portions one or two methylenegroups are optionally replaced independently of one another by NR^(b),O, S, CO, SO or SO₂, andwhen Y is hydrogen or C₁-C₆ alkyl, then both R⁸ and R⁹ are hydroxy;

R^(a) independently represents H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl or(C₁-C₄ alkyl)carbonyl, wherein alkyl and cycloalkyl groups or portionsoptionally may be partly or completely fluorinated;

R^(b) independently represents H, C₁-C₄ alkyl or (C₁-C₄ alkyl)carbonyl,wherein alkyl groups or portions optionally may be partly or completelyfluorinated;

R^(c) independently represents H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,CHR^(d)R^(e), SO₂R^(d), C(O)OR^(d) or C(O)NR^(d)R^(e), wherein alkyl andcycloalkyl groups optionally may be partly or completely fluorinated;and

R^(d) and R^(e) each independently represent H or C₁-C₆ alkyl, whereinalkyl groups optionally may be partly or completely fluorinated.

In another aspect, the present invention provides for compounds ofFormula I, wherein the substituent groups are defined as above, exceptwhen V represents oxygen, sulfur or a single bond, and W representsC₁-C₆ alkylene, then Y may also represent (C₃-C₁₀ cycloalkyl)C₁-C₄alkyl, wherein in the cycloalkyl portion of Y one or two methylenegroups are replaced independently of one another by O, S, CO, SO, SO₂ orNR^(b), and/or one or two methyne groups are replaced by N, wherein theheterocycle formed by said replacement is other than heteroaryl.

The style used above and hereinafter, in which a bond of a substituenton a phenyl group is shown ending near the center of the phenyl ring,denotes, unless otherwise stated, that this substituent may be bound toany free position of the phenyl group bearing a hydrogen atom.

The present invention includes all tautomers and stereoisomers ofcompounds of Formula I, either in admixture or in pure or substantiallypure form. The compounds of the present invention can have asymmetriccenters at the carbon atoms, and therefore the compounds of Formula Ican exist in diastereomeric or enantiomeric forms or mixtures thereof.All conformational isomers (e.g., cis and trans isomers) and all opticalisomers (e.g., enantiomers and diastereomers), racemic, diastereomericand other mixtures of such isomers, as well as solvates, hydrates,isomorphs, polymorphs and tautomers are within the scope of the presentinvention. Compounds according to the present invention can be preparedusing diastereomers, enantiomers or racemic mixtures as startingmaterials. Furthermore, diastereomer and enantiomer products can beseparated by chromatography, fractional crystallization or other methodsknown to those of skill in the art.

The present invention also provides for the prodrugs of compounds ofFormula I. Prodrugs of compounds of the invention include, bat are notlimited to, carboxylate esters, carbonate esters, hemi-esters,phosphorus esters, nitro esters, sulfate esters, sulfoxides, amides,carbamates, azo compounds, phosphamides, glycosides, ethers, acetals,and ketals. Prodrug esters and carbonates may be formed, for example, byreacting one or more hydroxyl groups of compounds of Formula I withalkyl, alkoxy or aryl substituted acylating reagents using methods knownto those of skill in the art to produce methyl carbonates, acetates,benzoates, pivalates and the like. Illustrative examples of prodrugesters of the compounds of the present invention include, but are notlimited to, compounds of Formula I having a carboxyl moiety wherein thefree hydrogen is replaced by C₁-C₄ alkyl, C₁-C₇ alkanoyloxymethyl,1-((C₁-C₅)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₅)alkanoyloxy)-ethyl,C₁-C₅ alkoxycarbonyloxymethyl, 1-((C₁-C₅)alkoxycarbonyloxy)ethyl,1-methyl-1-((C₁-C₅)alkoxycarbonyloxy)ethyl,N—((C₁-C₅)alkoxycarbonyl)aminomethyl,1-(N—((C₁-C₅)alkoxycarbonyl)amino)ethyl, 3-phthalidyl,4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (e.g., beta-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl. Oligopeptidemodifications and biodegradable polymer derivatives (as described, forexample, in Int. J. Pharm. 115, 61-67, 1995) are within the scope of theinvention. Methods for selecting and preparing suitable prodrugs areprovided, for example, in the following: T. Higuchi and V. Stella,“Prodrugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series,19′75; H. Bundgaard, “Design of Prodrugs,” Elsevier, 1985; and“Bioreversible Carriers in Drug Design,” ed. Edward Roche, AmericanPharmaceutical Association and Pergamon Press, 1987.

The present invention also provides for the pharmaceutically acceptablesalts of compounds of Formula I and prodrugs thereof. The acids that canbe used as reagents to prepare the pharmaceutically acceptable acidaddition salts of the basic compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions (such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate(1,1′-methylene-bis-2-hydroxy-3-naphthoate) salts). The bases that canbe used as reagents to prepare the pharmaceutically acceptable basesalts of the acidic compounds of the present invention are those thatform non-toxic base salts with such compounds, including, hut notlimited to, those derived from pharmacologically acceptable cations suchas alkali metal cations (e.g., potassium, lithium and sodium) andalkaline earth metal cations (e.g., calcium and magnesium), ammonium orwater-soluble amine addition salts such as N-methylglucamine(meglumine), and the lower alkanolammonium and other base salts ofpharmaceutically acceptable organic amines (e.g., methylamine,ethylamine, propylamine, dimethylamine, triethanolamine, diethylamine,t-butylamine, t-octylamine, trimethylamine, triethylamine,ethylenediamine, hydroxyethylamine, morpholine, piperazine,dehydroabietylamine, lysine and guanidine).

The present invention also includes isotopically-labeled compounds ofFormula I, wherein one or more atoms are replaced by one or more atomshaving specific atomic mass or mass numbers. Examples of isotopes thatcan be incorporated into compounds of the invention include, but are notlimited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine,sulfur, and chlorine (such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ¹⁸F, ³⁵Sand ³⁶Cl). Isotopically-labeled compounds of Formula I and prodrugsthereof, as well as isotopically-labeled, pharmaceutically acceptablesalts of compounds of Formula I and prodrugs thereof, are within thescope of the present invention. Isotopically-labeled compounds of thepresent invention are useful in assays of the tissue distribution of thecompounds and their prodrugs and metabolites; preferred isotopes forsuch assays include ³H and ¹⁴C. In addition, in certain circumstancessubstitution with heavier isotopes, such as deuterium (²H), can provideincreased metabolic stability, which offers therapeutic advantages suchas increased in vivo half-life or reduced dosage requirements.Isotopically-labeled compounds of this invention and prodrugs thereofcan generally be prepared according to the methods described herein bysubstituting an isotopically-labeled reagent for a non-isotopicallylabeled reagent.

Optionally, the compounds of Formula I may be reacted with a complexforming reagent, such as the D or L enantiomer of a natural amino acid,in a suitable solvent to form the corresponding crystalline complex,such as the amino acid complex, of the compound of Formula I. Amino acidcomplexes of compounds of Formula I may be formed by mixing an aminoacid with the purified compound in a suitable solvent or with a crudereaction mixture containing the compound and other reagents.

In preferred embodiments, V represents oxygen, sulfur, or a single bond.In particularly preferred embodiments, V represents oxygen or a singlebond.

In preferred embodiments, W represents C₁-C₆ alkylene, C₂-C₆ alkenylene,C₂-C₆ alkynylene, C₃-C₁₀ cycloalkylene, or (C₃-C₁₀ cycloalkylene)(C₁-C₆alkylene). In particularly preferred embodiments, W represents C₁-C₆alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene.

In preferred embodiments, X represents oxygen, sulfur, a single bond, orNR^(a). In particularly preferred embodiments, X represents oxygen or asingle bond.

In preferred embodiments, Y represents hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₄ alkyl, (C₁-C₄ alkyloxy)C₁-C₃ alkyl,(C₃-C₁₀ cycloalkyloxy)C₁-C₃ alkyl, (amino)C₁-C₃ alkyl, (C₁-C₄alkylamino)C₁-C₃ alkyl, (C₁-C₆ alkyl)carbonyl, (C₂-C₆ alkenyl)carbonyl,(C₂-C₆ alkynyl)carbonyl, (C₁-C₆ alkyl)sulfonyl, (C₂-C₆ alkenyl)sulfonyl,or (C₂-C₆ alkynyl)sulfonyl, wherein alkyl, alkenyl, alkynyl andcycloalkyl groups or portions optionally may be partly or completelyfluorinated and may be mono- or disubstituted by identical or differentsubstituents selected from chlorine, hydroxy, C₁-C₃ alkyl, C₁-C₃ alkoxy,and C₃-C₆ cycloalkyl, and in cycloalkyl groups or portions one or twomethylene groups are optionally replaced independently of one another byO, S, CO, SO, SO₂ or NR^(b), and one or two methyne groups areoptionally replaced by N. In particularly preferred embodiments, Yrepresents hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₁₀ cycloalkyl, or (C₁-C₄ alkyloxy)C₁-C₃ alkyl.

In preferred embodiments, Z represents oxygen, sulfur, or methyleneoptionally substituted with one to two substituents independentlyselected from halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyland C₃-C₆ cycloalkyloxy. In particularly preferred embodiments, Zrepresents methylene.

In preferred embodiments, R¹, R² and R³ each independently representhydrogen, halo, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkynyl,C₃-C₁₀ cycloalkyl, C₁-C₆ alkyloxy, or cyano. In particularly preferredembodiments, R¹, R² and R³ each independently represent hydrogen, haloor C₁-C₆ alkyl. In more particularly preferred embodiments, R¹represents hydrogen, halo or C₁-C₆ alkyl and R² and R³ both representhydrogen.

In preferred embodiments, R⁴ and R⁵ each independently representhydrogen, halo, hydroxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₁₀ cycloalkyl, C₁-C₆ alkyloxy, or cyano. In particularly preferredembodiments, R⁴ and R⁵ each independently represent hydrogen, halo orC₁-C₆ alkyl. In more particularly preferred embodiments, R⁴ and R⁵ bothrepresent hydrogen.

In preferred embodiments, R⁶, R⁷, R⁸ and R⁹ each independently representhydroxy, halo, C₁-C₆ alkyl, C₁-C₆ alkyloxy, (C₃-C₇)cycloalkyloxy,aryloxy or (C₃-C₇)cycloalkyl-(C₁-C₃)alkyloxy, wherein alkyl andcycloalkyl groups or portions may be partly or completely fluorinated.In particularly preferred embodiments, R⁶, R⁷, R⁸ and R⁹ each representhydroxy.

As noted above, Formula IA represents still other preferred embodiments:

wherein R¹ represents hydrogen, halo or C₁-C₆ alkyl; V represents oxygenor a single bond; W represents C₁-C₆ alkylene, C₂-C₆ alkenylene, C₂-C₆alkynylene, C₃-C₁₀ cycloalkylene, or (C₃-C₁₀ cycloalkylene)(C₁-C₆alkylene); X represents oxygen, a single bond, or NR^(a); and Yrepresents hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀cycloalkyl)C₁-C₄ alkyl, (C₁-C₄ alkyloxy)C₁-C₃ alkyl, (C₃-C₁₀cycloalkyloxy)C₁-C₃ alkyl, (amino)C₁-C₃ alkyl, (C₁-C₄ alkylamino)C₁-C₃alkyl, (C₁-C₆ alkyl)carbonyl, (C₂-C₆ alkenyl)carbonyl, (C₂-C₆alkynyl)carbonyl, (C₁-C₆ alkyl)sulfonyl, (C₂-C₆ alkenyl)sulfonyl, or(C₂-C₆ alkynyl)sulfonyl, wherein alkyl, alkenyl, alkynyl and cycloalkylgroups or portions optionally may be partly or completely fluorinatedand may be mono- or disubstituted by identical or different substituentsselected from chlorine, hydroxy, C₁-C₃ alkyl, C₁-C₃ alkoxy, and C₃-C₆cycloalkyl, and in cycloalkyl groups or portions one or two methylenegroups are optionally replaced independently of one another by O, S, CO,SO, SO₂ or NR^(b), and one or two methyne groups are optionally replacedby N.

In another aspect, the present invention includes the compounds ofFormula I and pharmaceutically acceptable salts, prodrugs and/orisotopically labeled compounds thereof, wherein alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl and heteroaryl groups or portions areoptionally substituted with one to three suitable substituents asdefined above.

In other aspects, the present invention provides intermediates andprocesses useful for preparing the intermediates below as well as thecompounds of Formula I, and pharmaceutically acceptable salts andprodrugs thereof.

Such processes are outlined in the following general preparative methodsdepicted in Schemes I-III (FIGS. 1-3), with more detailed particularexamples being presented below in the experimental section describingthe working examples. By following the general preparative methodsdiscussed below, or employing variations or alternative methods, thecompounds of the invention can be readily prepared by the use ofchemical reactions and procedures known to those of skill in the art.Unless otherwise specified, the variables (e.g., R groups) denotinggroups in the general methods described below have the meanings ashereinbefore defined.

Those of skill in the art will recognize that compounds of the inventionwith each described functional group are generally prepared using slightvariations of the below-listed general methods. Within the scope of eachmethod, functional groups which are suitable to the reaction conditionsare used. Functional groups which might interfere with certain reactionsare presented in protected forms where necessary, and the removal ofsuch protective groups is completed at appropriate stages by methodswell known to those skilled in the art.

In certain cases compounds of the invention can be prepared from othercompounds of the invention by elaboration, transformation, exchange andthe like of the functional groups present. Such elaboration includes,hut is not limited to, hydrolysis, reduction, oxidation, alkylation,acylation, esterification, amidation and dehydration. Suchtransformations can in some instances require the use of protectinggroups by the methods disclosed in T. W. Greene and Wuts, ProtectiveGroups in Organic Synthesis; Wiley: New York, (1999), and incorporatedherein by reference. Such methods would be initiated after synthesis ofthe desired compound or at another place in the synthetic route thatwould be readily apparent to one skilled in the art.

In another aspect, the present invention provides for syntheticintermediates useful for preparing the compounds of Formula I, andpharmaceutically acceptable salts and prodrugs thereof, according to thegeneral preparative methods discussed below and other processes known tothose of skill in the art.

When the following abbreviations and acronyms are used throughout thedisclosure, they have the following meanings: Ac₂O, acetic anhydride;AcOEt, ethyl acetate; AcOH, acetic acid; AIBN, azobis(isobutyronitrile);AlBr₃, aluminum bromide; AlCl₃, aluminum chloride; BBr₃, borontribromide; BP₃.Et₂O, boron trifluoride etherate; n-BuLi,n-butyllithium; s-BuLi, s-butyllithium; t-butyllithium; t-BuOK,potassium tert-butoxide; CaCl₂, calcium chloride; calc., calculated;CCl₄, carbon tetrachloride; CD₃OD, methanol-d₄; CDCl₃, chloroform-d;CF₃SO₃H, trifluoromethanesulfonic acid; CH₂Cl₂, methylene chloride;CH₂I₂, methylene iodide; CH₃CN, acetonitrile; (COCl)₂, oxalyl chloride;cod, 1,5-cyclooctadiene; Cs₂CO₃, cesium carbonate; DAST,(diethylamino)sulfur trifluoride; DCM, dichloromethane; DMAP,4-dimethylaminopyridine; DMEM, Dulbecco's Modified Eagle Medium; DMF,N,N-dimethylformamide; DMP, Dess-Martin periodinane; DMSO,dimethylsulfoxide; EA, ethyl acetate; EDCI,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; eq,equivalents; Et, ethyl; Et₃N, triethylamine; Et₃SiH, triethylsilane;Et₃SiO, triethylsilyloxy; EtOAc, ethyl acetate; EtOH, ethanol; FBS,fetal bovine serum; FSO₂CF₂CO₂H, 2,2-difluoro-2-(fluorosulfonyl)aceticacid; h, hour; H₂, hydrogen gas; H₂SO₄, sulfuric acid; Hepes,4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; ¹H NMR, protonnuclear magnetic resonance; HOBt, 1-hydroxybenzotriazole; HPLC, highperformance liquid chromatography; K₂CO₃, potassium carbonate; K₂CrO₇,potassium dichromate; KN(TMS)₂, potassium bis(trimethylsilyl)amide; KOH,potassium hydroxide; LC-ESI-MS, chromatography electrospray ionizationmass spectrometry; LC-MS, liquid chromatography-mass spectroscopy; Lg,leaving group; LiOH.H₂O, lithium hydroxide monohydrate; Me, methyl;MeCN, acetonitrile; MeOH, methanol; MeSO₃H, methanesulfonic acid; Mg,magnesium; MgCl₂, magnesium chloride; min, minute; MS ESI, massspectroscopy with electrospray ionization; MsOH, methanesulfonic acid;NaBH₃CN, sodium cyanoborohydride; NaH, sodium hydride; NaHCO₃, sodiumbicarbonate; NaHSO₃, sodium bisulfite; NaOAc, sodium acetate; NaOH,sodium hydroxide; Na₂SO₄, sodium sulfate; NBS, N-bromosuccinimide; NCS,N-chlorosuccinimide; NH₄Cl, ammonium chloride; NIS, N-iodosuccinimide;O₃, ozone; Pd/C, palladium on carbon; PdCl₂, palladium (II) chloride;PE, petroleum ether; Ph, phenyl; Ph₃PCH₃I (or Ph₃PMeI),methyltriphenylphosphonium iodide; POCl₃, phosphorus oxychloride; PPh₃,triphenylphosphine; R_(f), retention factor; SnBu₃, tributyltin; SOCl₂,thionyl chloride; TBAI, tetrabutylammonium iodide; TFA, trifluoroaceticacid; THF, tetrahydrofuran; TLC, thin layer chromatography; TMS,trimethylsilyl; TMSCN, trimethylsilyl cyanide; Tris,trishydroxymethylaminomethane (or2-amino-2-(hydroxymethyl)propane-1,3-diol); TsCl, toluenesulfonylchloride; TsOH, toluenesulfonic acid; ZnEt₂, diethyl zinc.

General Synthesis Method of Scheme I

Inventive compounds of formula 12 can be conveniently prepared accordingto the reaction sequences as shown in Scheme I (FIG. 1). Acid 1, whichmay be commercially available or prepared according to conventionalmethods known to those of skill in the art, is converted to acidchloride 2 by an acylation agent such as oxalyl chloride, SOCl₂, POCl₃or the like. Intermediate 2 is reacted with alkoxybenzene 3 underconditions aided by Lewis acid, such as AlCl₃ or AlBr₃, to provideketone 4. The ketone group of intermediate 4 is reduced to methylenewith a reducing agent such as Et₃SiH in the present of a Lewis acid suchas BF₃.Et₂O or TFA, and treatment with Lewis acid such as BBr₃ to givephenol 5. Intermediate 6 can be obtained by coupling with theelectrophilic reagent Lg-W-X-Y, where Lg denotes a suitable leavinggroup, in the presence of base such as K₂CO₃, Cs₂CO₃, NaOH or the like.

Alternatively, acid 1 can be converted to Weinreb amide 7 by couplingwith NHMe(OMe). Intermediate 4 can then be obtained by treatment ofWeinreb amide 7 with intermediate 8, bearing a metal coupling reagentsuch as Grignard reagent.

Alternatively, intermediate 6 can also be obtained by coupling ofWeinreb amide 7 with Grignard reagent 9, followed by reduction of theketone group of product 10 with Et₃SiH in the presence a Lewis acid suchas BF₃.Et₂O or TFA.

Intermediate 6 is condensed with ketone 11 after treatment withactivating reagent, such as n-BuLi or t-BuOK, and then reduced withalkylsilane or other reductant in the presence of acid, such as TFA,MeSO₃H or BF₃.Et₂O, to generate the inventive compounds of formula 12.

General Synthesis Method of Scheme II

Inventive compounds of formula 12 can also be conveniently preparedaccording to a reaction sequence as shown in Scheme II (FIG. 2). Theketone group of intermediate 4 is reduced to methylene with a reducingagent such as Et₃SiH in the presence of a Lewis acid such as BF₃.Et₂O orTFA. Intermediate 13 is condensed with ketone 11 after treatment withactivating reagent, such as n-BuLi or t-BuOK, and then reduced withalkylsilane or other reductant in the presence of acid, such as TFA,MeSO₃H or BF₃.Et₂O, to give the intermediate 14. Treatment of 14 with aLewis acid such as BBr₃ gives phenol 15, and then coupling with theelectrophilic reagent Lg-W-X-Y in the presence of base, such as K₂CO₃,Cs₂CO₃, NaOH or the like, gives the inventive compounds of formula 12.

General Synthesis Method of Scheme III

Inventive compounds of formula 12 can also be prepared according to areaction sequence as shown in Scheme III (FIG. 3). Treatment ofintermediate 16 with a base such as n-BuL, s-BuLi or t-BuLi, or Mg in asolvent such as THF to form Grignard reagent, followed by addition tointermediate 11 and treatment of the corresponding product with Lewisacid such as Et₃SiH provides intermediate 17. Halogenation of 17 withNCS, NBS or NIS provides intermediate 18. Stifle coupling of 9 withintermediate 18 gives inventive compounds of formula 12.

Pharmaceutical Compositions and Methods of Use

The present invention further provides a pharmaceutical compositioncomprising an effective amount of a compound or mixture of compounds ofFormula I, or a pharmaceutically acceptable salt or prodrug thereof, ina pharmaceutically acceptable carrier.

A compound of this invention can be incorporated into a variety offormulations for therapeutic administration. More particularly, acompound of the present invention can be formulated into pharmaceuticalcompositions, together or separately, by formulation with appropriatepharmaceutically acceptable carriers or diluents, and can be formulatedinto preparations in solid, semi-solid, liquid or gaseous forms, such astablets, capsules, pills, powders, granules, dragees, gels, slurries,ointments, solutions, suppositories, injections, inhalants and aerosols.As such, administration of a compound of the present invention can beachieved in various ways, including oral, buccal, parenteral,intravenous, intradermal (e.g., subcutaneous, intramuscular),transdermal, etc., administration. Moreover, the compound can beadministered in a local rather than systemic manner, thr example, in adepot or sustained release formulation.

Suitable formulations for use in the present invention are tbund inRemington: The Science and Practice of Pharmacy, 21^(st) Ed., Germaro,Lippencott Williams & Wilkins (2003), which is hereby incorporatedherein by reference. The pharmaceutical compositions described hereincan be manufactured in a manner that is known to those of skill in theart, i.e., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orlyophilizing processes. The following methods and excipients are merelyexemplary and are in no way limiting.

In one preferred embodiment, a compound of the present invention isprepared thr delivery in a sustained-release, controlled release,extended-release, timed-release or delayed-release formulation, forexample, in semipermeable matrices of solid hydrophobic polymerscontaining the therapeutic agent. Various types of sustained-releasematerials have been established and are well known by those skilled inthe art. Current extended-release formulations include film-coatedtablets, multiparticulate or pellet systems, matrix technologies usinghydrophilic or lipophilic materials and wax-based tablets withpore-forming excipients (see, for example, Huang, et al. Drug Dev. IndPharm. 29:79 (2003); Pearnchob, et al. Drug Dev. Ind. Pharm. 29:925(2003); Maggi, et al. Eur. J. Pharm. Biopharm. 55:99 (2003); Khanvilkar,et al., Drug Dev. Ind. Pharm, 228:601 (2002); and Schmidt, et al., Int.J. Pharm, 216:9 (2001)). Sustained-release delivery systems can,depending on their design, release the compounds over the course ofhours or days, for instance, over 4, 6, 8, 10, 12, 16, 20, 24 hours ormore. Usually, sustained release formulations can be prepared usingnaturally-occurring or synthetic polymers, thr instance, polymeric vinylpyrrolidones, such as polyvinyl pyrrolidone (PVP); carboxyvinylhydrophilic polymers; hydrophobic and/or hydrophilic hydrocolloids, suchas methylcellulose, ethylcellulose, hydroxypropylcellulose, andhydroxypropylmethylcellulose; and carboxypolymethylene.

The sustained or extended-release formulations can also be preparedusing natural ingredients, such as minerals, including titanium dioxide,silicon dioxide, zinc oxide, and clay (see, U.S. Pat. No. 6,638,521,herein incorporated by reference). Exemplified extended releaseformulations that can be used in delivering a compound of the presentinvention include those described in U.S. Pat. Nos. 6,635,680;6,624,200; 6,613,361; 6,613,358, 6,596,308; 6,589,563; 6,562,375;6,548,084; 6,541,020; 6,537,579; 6,528,080 and 6,524,621, each of whichis hereby incorporated herein by reference. Controlled releaseformulations of particular interest include those described in U.S. Pat.Nos. 6,607,751; 6,599,529; 6,569,463; 6,565,883; 6,482,440; 6,403,597;6,319,919; 6,150,354; 6,080,736; 5,672,356; 5,472,704; 5,445,829;5,312,817 and 5,296,483, each of which is hereby incorporated herein byreference. Those skilled in the art will readily recognize otherapplicable sustained release formulations.

For oral administration, a compound of the present invention can beformulated readily by combining with pharmaceutically acceptablecarriers that are well known in the art. Such carriers enable thecompounds to be formulated as tablets, pills, dragees, capsules,emulsions, lipophilic and hydrophilic suspensions, liquids, gels,syrups, slurries, suspensions and the like, for oral ingestion by apatient to be treated. Pharmaceutical preparations for oral use can beobtained by mixing the compounds with a solid excipient, optionallygrinding a resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain tablets ordragee cores. Suitable excipients are, in particular, fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents can beadded, such as a cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds can be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers can be added. All formulations fororal administration should be in dosages suitable for suchadministration.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds can be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Forinjection, the compound can be formulated into preparations bydissolving, suspending or emulsifying them in an aqueous or nonaqueoussolvent, such as vegetable or other similar oils, synthetic aliphaticacid glycerides, esters of higher aliphatic acids or propylene glycol;and if desired, with conventional additives such as solubilizers,isotonic agents, suspending agents, emulsifying agents, stabilizers andpreservatives. Preferably, a compound of the invention can be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hanks's solution, Ringer's solution, or physiological salinebuffer. Formulations for injection can be presented in unit dosage form,e.g., in ampules or in multi-dose containers, with an addedpreservative. The compositions can take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and can containformulatory agents such as suspending, stabilizing and/or dispersingagents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds can be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions can contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension can also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient can be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.For topical administration, the agents are formulated into ointments,creams, salves, powders and gels. In one embodiment, the transdermaldelivery agent can be DMSO. Transdermal delivery systems can include,e.g., patches. For transmucosal administration, penetrants appropriateto the barrier to be permeated are used in the formulation. Suchpenetrants are generally known in the art. Exemplified transdermaldelivery formulations that can find use in the present invention includethose described in U.S. Pat. Nos. 6,589,549; 6,544,548; 6517,864;6,512,010; 6,465,006; 6,379,696; 6,312,717 and 6,310,177, each of whichare hereby incorporated herein by reference.

For buccal administration, the compositions can take the form of tabletsor lozenges formulated in conventional manner.

In addition to the formulations described previously, a compound of thepresent invention can also be formulated as a depot preparation. Suchlong acting formulations can be administered by implantation (forexample subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds can be formulated withsuitable polymeric or hydrophobic materials (for example as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

The pharmaceutical compositions also can comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in atherapeutically effective amount. The present invention alsocontemplates pharmaceutical compositions comprising the compounds ofFormula in admixture with an effective amount of other therapeuticagents as combination partners, particularly those used for treatingdiseases and conditions which can be affected by SGLT inhibition, suchas antidiabetic agents, lipid-lowering/lipid-modulating agents, agentsfor treating diabetic complications, anti-obesity agents,antihypertensive agents, antihyperuricemic agents, and agents fortreating chronic heart failure, atherosclerosis or related disorders. Aneffective amount of the compound and/or combination partner will, ofcourse, be dependent on the subject being treated, the severity of theaffliction and the manner of administration. Determination of aneffective amount is well within the capability of those skilled in theart, especially in light of the detailed disclosure provided herein.Generally, an efficacious or effective amount of a compound isdetermined by first administering a low dose or small amount, and thenincrementally increasing the administered dose or dosages until adesired therapeutic effect is observed in the treated subject, withminimal or no toxic side effects. Applicable methods for determining anappropriate dose and dosing schedule for administration of the presentinvention are described, for example, in Goodman and Gilman's ThePharmacological Basis of Therapeutics, 11^(th) Ed., Brunton, Lazo andParker, Eds., McGraw-Hill (2006), and in Remington: The Science andPractice of Pharmacy, 21^(st) Ed., Gennaro, Ed., Lippencott Williams &Wilkins (2003), both of which are hereby incorporated herein byreference.

The present invention further provides methods of using the compounds ofFormula I for the prevention and treatment of disease. In one embodimentthe invention provides a method of treating type 1 and type 2 diabetesmellitus, hyperglycemia, diabetic complications (such as retinopathy,nephropathy, neuropathy, ulcers, micro- and macroangiopathies, gout anddiabetic foot disease), insulin resistance, metabolic syndrome (SyndromeX), hyperinsulinemia, hypertension, hyperuricemia, obesity, edema,dyslipidemia, chronic heart failure, atherosclerosis and relateddiseases, which comprises administering an effective amount of acompound or mixture of compounds of Formula I, or a pharmaceuticallyacceptable salt or prodrug thereof, to a subject in need thereof. Inanother embodiment the invention provides a method of using a compoundor mixture of compounds of Formula I, or a pharmaceutically acceptablesalt or prodrug thereof, for the preparation of a medicament fortreating type 1 and type 2 diabetes mellitus, hyperglycemia, diabeticcomplications, insulin resistance, metabolic syndrome, hyperinsulinemia,hypertension, hyperuricemia, obesity, edema, dyslipidemia, chronic heartfailure, atherosclerosis and related diseases.

The present invention also contemplates the use of the compounds ofFormula I, or pharmaceutically acceptable salts or prodrugs thereof incombination with other therapeutic agents, particularly those used fortreating the above-mentioned diseases and conditions, such asantidiabetic agents, lipid-lowering/lipid-modulating agents, agents fortreating diabetic complications, anti-obesity agents, antihypertensiveagents, antihyperuricemic agents, and agents for treating chronic heartfailure, atherosclerosis or related disorders. Those skilled in the artwill appreciate that other therapeutic agents discussed below can havemultiple therapeutic uses and the listing of an agent in one particularcategory should not be construed to limit in any way its usefulness incombination therapy with compounds of the present invention.

Examples of antidiabetic agents suitable for use in combination withcompounds of the present invention include insulin and insulin mimetics,sulfonylureas (such as acetohexamide, carbutamide, chlorpropamide,glibenclamide, glibornuride, gliclazide, glimepiride, glipizide,gliquidone, glisoxepide, glyburide, glyclopyramide, tolazamide,tolcyclamide, tolbutamide and the like), insulin secretion enhancers(such as JTT-608, glybuzole and the like), biguanides (such asmetformin, buformin, phenformin and the like), sulfonylurea/biguanidecombinations (such as glyburide/metformin and the like), meglitinides(such as repaglinide, nateglinide, mitiglinide and the like),thiazolidinediones (such as rosiglitazone, pioglitazone, isaglitazone,netoglitazone, rivoglitazone, balaglitazone, darglitazone, CLX-0921 andthe like), thiazolidinedione/biguanide combinations (such aspioglitazone/metformin and the like), oxadiazolidinediones (such asYM440 and the like), peroxisome proliferator-activated receptor(PPAR)-gamma agonists such as farglitazar, metaglidasen, MBX-2044, GI262570, GW1929, GW7845 and the like), PPAR-alpha/gamma dual agonists(such as muraglitazar, naveglitazar, tesaglitazar, peliglitazar,JTT-501, GW-409544, GW-501516 and the like), PRAR-alpha/gamma/delta panagonists (such as PLX204, CilaxoSmithKline 625019, GlaxoSmithKline677954 and the like), retinoid X receptor agonists (such as ALRT-268,AGN-4204, MX-6054, AGN-194204, LG-100754, bexarotene and the like),alpha-glucosidase inhibitors (such as acarbose, miglitol and the like),stimulants of insulin receptor tyrosine kinase (such as TER-17411,L-783281, KRX-613 and the like), tripeptidyl peptidase II inhibitors(such as UCL-1397 and the like), dipeptidyl peptidase IV inhibitors(such as sitagliptin, vildagliptin, denagliptin, saxagliptin,NVP-DPP728, P93/01, P32/98, FE 99901, TS-021, TSL-225, GRC8200,compounds described in U.S. Pat. Nos. 6,869,947; 6,727,261; 6,710,040;6,432,969; 6,172,081; 6,011,155 and the like), protein tyrosinephosphatase-1B inhibitors (such as KR61639, IDD-3, PIP-3848, PIP-112,OC-86839, PNU-177496, compounds described in Vats, R. K., et al.,Current Science, Vol. 88, No. 2, 25 Jan. 2005, pp. 241-249, and thelike), glycogen phosphorylase inhibitors (such as NN-4201, CP-368296 andthe like), glucose-6-phosphatase inhibitors, fructose 1,6-bisphosphataseinhibitors (such as CS-917, MB05032 and the like), pyruvatedehydrogenase inhibitors (such as AZD-7545 and the like), imidazolinederivatives (such as BL11282 and the like), hepatic gluconeogenesisinhibitors (such as FR-225659 and the like), D-chiroinositol, glycogensynthase kinase-3 inhibitors (such as compounds described in Vats, R.K., et al., Current Science, Vol. 88, No. 2, 25 Jan. 2005, pp. 241-249,and the like), incretin mimetics (such as exenatide and the like),glucagon receptor antagonists (such as BAY-27-9955, NN-2501, NNC-92-1687and the like), glucagon-like peptide-1 (GLP-1), GLP-1 analogs (such asliraglutide, CJC-1131, AVE-0100 and the like), GLP-1 receptor agonists(such as AZM-134, LY-315902, GlaxoSmithKline 716155 and the like),amylin, amylin analogs and agonists (such as pramlintide and the like),fatty acid binding protein (aP2) inhibitors (such as compounds describedin U.S. Pat. Nos. 6,984,645; 6,919,323; 6,670,380; 6,649,622; 6,548,529and the like), beta-3 adrenergic receptor agonists (such as solabegron,CL-316243, L-771047, FR-1491.75 and the like), and other insulinsensitivity enhancers (such as reglixane, ONO-5816, MBX-102, CRE-1625,FK-614, CLX-0901, CRE-1633, NN-2344, BM-13125, BM-501050, HQL-975,CLX-0900, MBX-668, MBX-675, S-15261, GW-544, AZ-242, LY-510929,AR-H049020, GW-501516 and the like).

Examples of agents for treating diabetic complications suitable for usein combination with compounds of the present invention include aldosereductase inhibitors (such as epalrestat, imirestat, tolrestat,minalrestat, ponalrestat, zopolrestat, fidarestat, ascorbyl gamolenate,ADN-138, BAL-ARI8, ZD-5522, ADN-311, OP-1447, IDD-598, risarestat,zenarestat, methosorbinil, AL-1567, M-16209, TAT, AD-5467. AS-3201,NZ-314, SG-210, JTT-811, lindolrestat, sorbinil and the like),inhibitors of advanced glycation end-products (AGE) formation (such aspyridoxamine, OPB-9195, ALT-946, ALT-711, pimagedine and the like), AGEbreakers (such as ALT-711 and the like), sulodexide,5-hydroxy-1-methylhydantoin, insulin-like growth factor-I,platelet-derived growth factor, platelet-derived growth factor analogs,epidermal growth factor, nerve growth factor, uridine, protein kinase Cinhibitors (such as ruboxistaurin, midostaurin and the like), sodiumchannel antagonists (such as mexiletine, oxcarbazepine and the like),nuclear factor-kappaB (NF-kappaB) inhibitors (such as dexlipotam and thelike), lipid peroxidase inhibitors (such as tirilazad mesylate and thelike), N-acetylated-alpha-linked-acid-dipeptidase inhibitors (suchGPI-5232, GPI-5693 and the like), and carnitine derivatives (such ascarnitine, levacecamine, levocarnitine, ST-261 and the like).

Examples of antihyperuricemic agents suitable for use in combinationwith compounds of the present invention include uric acid synthesisinhibitors (such as allopurinol, oxypurinol and the like), uricosuricagents (such as probenecid, sulfinpyrazone, benzbromarone and the like)and urinary alkalinizers (such as sodium hydrogen carbonate, potassiumcitrate, sodium citrate and the like).

Examples of lipid-lowering/lipid-modulating agents suitable for use incombination with compounds of the present invention includehydroxymethylglutaryl coenzyme A reductase inhibitors (such asacitemate, atorvastatin, bervastatin, carvastatin, cerivastatin,colestolone, crilvastatin, dalvastatin, fluvastatin, glenvastatin,lovastatin, mevastatin, nisvastatin, pitavastatin, pravastatin,ritonavir, rosuvastatin, saquinavir, simvastatin, visastatin, SC-45355,SQ-33600, CP-83101, BB-476, L-669262, S-2468, DMP-565, U-20685,BMS-180431, BMY-21950, compounds described in U.S. Pat. Nos. 5,753,675;5,691,322; 5,506,219; 4,680,237; 4,647,576; 4,613,610; 4,499,289 and thelike), fibric acid derivatives (such as gemfibrozil, fenofibrate,bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate,clofibrate, etofibrate, nicofibrate, pirifibrate, ronifibrate,simfibrate, theofibrate, AHL-157 and the like), PPAR-alpha agonists(such as GlaxoSmithKline 590735 and the like), PPAR-delta agonists (suchas GlaxoSmithKline 501516 and the like), acyl-coenzyme A:cholesterolacyltransferase inhibitors (such as avasimibe, eflucimibe, eldacimibe,lecimibide, NTE-122, MCC-147, PD-132301-2, C1-1011, DUP-129, U-73482,U-76807, TS-962, RP-70676, P-06139, CP-113818, RP-73163, FR-129169,FY-038, EAB-309, KY-455, LS-3115, FR-145237, T-2591, J-104127, R-755,FCE-27677, FCE-28654, YIC-C8-434, CI-976, RP-64477, F-1394, CS-505,CL-283546, YM-17E, 447C88, YM-750, E-5324, KW-3033, HL-004 and thelike), probucol, thyroid hormone receptor agonists (such asliothyronine, levothyroxine, KB-2611, GC-1 and the like), cholesterolabsorption inhibitors (such as ezetimibe, SCH48461 and the like),lipoprotein-associated phospholipase A2 inhibitors (such as rilapladib,darapladib and the like), microsomal triglyceride transfer proteininhibitors (such as CP-346086, BMS-201038, compounds described in U.S.Pat. Nos. 5,595,872; 5,739,135; 5,712,279; 5,760,246; 5,827,875;5,885,983; 5,962,440; 6,197,798; 6,617,325; 6,821,967; 6,878,707 and thelike), low density lipoprotein receptor activators (such as LY295427,MD-700 and the like), lipoxygenase inhibitors (such as compoundsdescribed in WO 97/12615, WO 97/12613, WO 96/38144 and the like),carnitine palmitoyl-transferase inhibitors (such as etomoxir and thelike), squalene synthase inhibitors (such as YM-53601, TAK-475,SDZ-268-198, BMS-188494, A-87049, RPR-101821, ZD-9720, RPR-107393,ER-27856, compounds described in U.S. Pat. Nos. 5,712,396; 4,924,024;4,871,721 and the like), nicotinic acid derivatives (such as acipimox,nicotinic acid, ricotinamide, nicomol, niceritrol, nicorandil and thelike), bile acid sequestrants (such as colestipol, cholestyramine,colestilan colesevelam, GT-102-279 and the like), sodium/bile acidcotransporter inhibitors (such as 264W94, S-8921, SD-5613 and the like),and cholesterol ester transfer protein inhibitors (such as torcetrapib,JTT-705, PNU-107368E, SC-795, CP-529414 and the like).

Examples of anti-obesity agents suitable for use in combination withcompounds of the present invention include serotonin-norepinephrinereuptake inhibitors (such as sibutramine, milnacipran, mirtazapine,venlafaxine, duloxetine, desvenlafaxine and the like),norepinephrine-dopamine reuptake inhibitors (such as radafaxine,bupropion, amineptine and the like), selective serotonin reuptakeinhibitors (such as citalopram, escitalopram, fluoxetine, fluvoxamine,paroxetine, sertraline and the like), selective norepinephrine reuptakeinhibitors (such as reboxetine, atomoxetine and the like),norepinephrine releasing stimulants (such as rolipram, YM-992 and thelike), anorexiants (such as amphetamine, methamphetamine,dextroamphetamine, phentermine, benzphetamine, phendimetrazine,phenmetrazine, diethylpropion, mazindol, fenfluramine, dexfenfluramine,phenylpropanolamine and the like), dopamine agonists (such as ER-230,doprexin, bromocriptine mesylate and the like), H₃-histamine antagonists(such as impentamine, thioperamide, ciproxifan, clobenpropit, GT-2331,GT-2394, A-331440, and the like), 5-HT2c receptor agonists (such as,1-(m-chlorophenyl)piperazine (m-CPP), mirtazapine, APD-356 (lorcaserin),SCA-136 (vabicaserin), ORG-12962, ORG-37684, ORG-36262, ORG-8484,Ro-60-175, Ro-60-0332, VER-3323, VER-5593, VER-5384, VER-8775,LY-448100, WAY-161503, WAY-470, WAY-163909. MK-212, BVT.933, YM-348,IL-639, IK-264, ATH-88651, ATHX-105 and the like (see, e.g. Nilsson B M,J. Med. Chem. 2006, 49:4023-4034)), beta-3 adrenergic receptor agonists(such as L-796568, CGP 12177, BRL-28410, SR-58611A, ICI-198157, ZD-2079,BMS-194449, BRL-37344, CP-331679, CP-331648, CP-114271, L-750355,BMS-187413, SR-59062A, BMS-210285, LY-377604, SWR-0342SA, AZ-40140,SB-226552, D-7114, BRL-35135, FR-149175, BRL-26830A, CL-316243, AJ-9677,GW-427353, N-5984, GW-2696 and the like), cholecystokinin agonists (suchas SR-146131, SSR-125180, BP-3.200, A-71623, A-71378, FPL-15849,GI-248573, GW-7178, GI-181771, GW-7854, GW-5823, and the like),antidepressant/acetylcholinesterase inhibitor combinations (such asvenlafaxine/rivastigmine, sertraline/galanthamine and the like), lipaseinhibitors (such as orlistat, ATL-962 and the like), anti-epilepticagents (such as topiramate, zonisamide and the like), leptin, leptinanalogs and leptin receptor agonists (such as LY-355101 and the like),neuropeptide Y (NPY) receptor antagonists and modulators (such asSR-120819-A, PD-160170, NOD-95-1, BIBP-3226, 1229-U-91, CGP-71683,BIBO-3304, CP-671906-01, J-115814 and the like), ciliary neurotrophicfactor (such as Axokine and the like), thyroid hormone receptor-betaagonists (such as KB-141, GC-1, GC-24, GB98/284425 and the like),cannabinoid CBI receptor antagonists (such as rimonabant, SR147778, SLV319 and the like (see, e.g., Antel J et al., J. Med. Chem. 2006,49:4008-4016)), melanin-concentrating hormone receptor antagonists (suchas GlaxoSmithKline 803430X, GlaxoSmithKline 856464, SNAP-7941, T-226296and the like (see, e.g., Handlon A L and Zhou H, J. Med. Chem. 2006,49:4017-4022)), melanocortin-4 receptor agonists (including PT-15,Ro27-3225, THIQ, NBI 55886, NBI 56297, NBI 56453, NBI 58702, NBI 58704,MB243 and the like (see, e.g., Nargund R P et al., J. Med. Chem. 2006,49:4035-4043)), selective muscarinic receptor antagonists such astelenzepine, pirenzepine and the like), opioid receptor antagonists(such as naltrexone, methylnaltrexone, nalmefene, naloxone, alvimopan,norbinaltorphimine, nalorphine and the like), and combinations thereof.

Examples of antihypertensive agents and agents for treating chronicheart failure, atherosclerosis or related diseases suitable for use incombination with compounds of the present invention include bimoclomol,angiotensin-converting enzyme inhibitors (such as captopril, enalapril,fosinopril, lisinopril, perindopril, quinapril, ramipril and the like),neutral endopeptidase inhibitors (such as thiorphan, omapatrilat,MDL-100240, fasidotril, sampatrilat, GW-660511, mixanpril, SA-7060,E-4030, SIN-306, ecadotril and the like), angiotensin II receptorantagonists (such as candesartan cilexetil, eprosartan, irbesartan,losartan, olmesartan medoxomil, telmisartan, valsartan, tasosartan,enoltasosartan and the like), endothelin-converting enzyme inhibitors(such as CGS 35066, CGS 26303, CGS-31447, SM-19712 and the like),endothelin receptor antagonists (such as tracleer, sitaxsentan,ambrisentan, L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201, SB-215355,PD-180988, BMS-193884, darusentan, TBC-3711, bosentan, tezosentan,J-104132, YM-598, S-0139, SB-234551, RPR-118031A, ATZ-1993, RO-61-1790,ABT-546, enlasentan, BMS-207940 and the like), diuretic agents (such ashydrochlorothiazide, bendroflumethiazide, trichlormethiazide,indapamide, metolazone, furosemide, bumetanide, torsemide,chlorthalidone, metolazone, cyclopenthiazide, hydroflumethiazide,tripamide, mefruside, benzylhydrochlorothiazide, penflutizide,methyclothiazide, azosemide, etacrynic acid, torasemide, piretanide,meticrane, potassium canrenoate, spironolactone, triamterene,aminophylline, cicletanine, LLU-alpha, PNU-80873A, isosorbide,D-mannitol, D-sorbitol, fructose, glycerin, acetazolamide,methazolamide, FR-179544, OPC-31260, lixivaptan, conivaptan and thelike), calcium channel antagonists (such as amlodipine, bepridil,diltiazem, felodipine, isradipine, nicardipen, verapamil, S-verapamil,aranidipine, efonidipine, barnidipine, benidipine, manidipine,cilnidipine, nisoldipine, nitrendipine, nifedipine, nilvadipine,felodipine, pranidipine, lercanidipine, isradipine, elgodipine,azelnidipine, lacidipine, vatanidipine, lemildipine, diltiazem,clentiazem, fasudil, bepridil, gallopamil and the like), vasodilatingantihypertensive agents (such as indapamide, todralazine, hydralazine,cadralazine, budralazine and the like), beta Mockers (such asacebutolol, bisoprolol, esmolol, propanolol, atenolol, labetalol,carvedilol, metoprolol and the like), sympathetic blocking agents (suchas amosulalol, terazosin, bunazosin, prazosin, doxazosin, propranolol,atenolol, metoprolol, carvedilol, nipradilol, celiprolol, nebivolol,betaxolol, pindolol, tertatolol, bevantolol, timolol, carteolol,bisoprolol, bopindolol, nipradilol, penbutolol, acebutolol, tilisolol,nadolol, urapidil, indoramin and the like), alpha-2-adrenoceptoragonists (such as clonidine, methyldopa, CHF-1035, guanabenz acetate,guanfacine, moxonidine, lofexidine, talipexole and the like), centrallyacting antihypertensive agents (such as reserpine and the like),thrombocyte aggregation inhibitors (such as warfarin, dicumarol,phenprocoumon, acenocoumarol, anisindione, phenindione, ximelagatran andthe like), and antiplatelets agents (such as aspirin, clopidogrel,ticlopidine, dipyridamole, cilostazol, ethyl icosapentate, sarpogrelate,dilazep, trapidil, beraprost and the like).

Furthermore, in another aspect, the invention provides for apharmaceutical composition comprising effective amounts of a compound ormixture of compounds of Formula I, or a pharmaceutically acceptable saltor prodrug thereof and at least one member selected from the group oftherapeutic agents listed above as combination partners, in apharmaceutically acceptable carrier.

The treatment of the present invention can be administeredprophylactically to prevent or delay the onset or progression of adisease or condition (such as hyperglycemia), or therapeutically toachieve a desired effect (such as a desired level of serum glucose) fora sustained period of time.

The compounds of the present invention can be administered to a subject,e.g., a human patient, a domestic animal such as a cat or a dog,independently or together with a combination partner, in the form oftheir pharmaceutically acceptable salts or prodrugs, or in the form of apharmaceutical composition where the compounds and/or combinationpartners are mixed with suitable carriers or excipient(s) in atherapeutically effective amount, Consequently, a compound or mixture ofcompounds of Formula I, or a pharmaceutically acceptable salt or prodrugthereof, and an additional active agent to be combined therewith, can bepresent in a single formulation, for example a capsule or tablet, or intwo separate formulations, which can be the same or different, forexample, in the form of a kit comprising selected numbers of doses ofeach agent.

The appropriate dosage of compound will vary according to the chosenroute of administration and formulation of the composition, among otherfactors, such as patient response. The dosage can be increased ordecreased over time, as required by an individual patient. A patientinitially may be given a low dose, which is then increased to anefficacious dosage tolerable to the patient. Typically, a useful dosagefor adults may be from 1 to 2000 mg, preferably to 200 mg, whenadministered by oral route, and from 0.1 to 100 mg, preferably 1 to 30mg, when administered by intravenous route, in each case administeredfrom 1 to 4 times per day. When a compound of the invention isadministered in combination with another therapeutic agent, a usefuldosage of the combination partner may be from 20% to 100% of thenormally recommended dose.

Dosage amount and interval can be adjusted individually to provideplasma levels of the active compounds which are sufficient to maintaintherapeutic effect. Preferably, therapeutically effective serum levelswill be achieved by administering single daily doses, but efficaciousmultiple daily dose schedules are included in the invention. In cases oflocal administration or selective uptake, the effective localconcentration of the drug may not be related to plasma concentration.One having skill in the art will be able to optimize therapeuticallyeffective local dosages without undue experimentation.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Any conflict between any reference citedherein and the teaching of this specification is to be resolved in favorof the latter. Similarly, any conflict between an art-recognizeddefinition of a word or phrase and a definition of the word or phrase asprovided in this specification is to be resolved in favor of the latter.Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to those of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications can be made thereto without departing from the spiritor scope of the appended claims. The invention will be described ingreater detail by way of specific examples.

EXAMPLES

The following examples are offered for illustrative purposes, and arenot intended to limit the invention in any manner. Those of skill in theart will readily recognize a variety of noncritical parameters which canbe changed or modified to yield essentially the same results.

The names of compounds shown in the following examples were derived fromthe structures shown using the CambridgeSoft Struct=Name algorithm asimplemented in ChemDraw Ultra version 10.0. Unless otherwise indicated,the structures of compounds synthesized in the examples below wereconfirmed using the following procedures:

(1) Gas chromatography—mass spectra with electrospray ionization (MSESI) were obtained with an Agilent 5973N mass spectrometer equipped withan Agilent 6890 gas chromatograph with an HP-5 MS column (0.25 μmcoating; 30 m×0.25 mm). The ion source was maintained at 230° C. andspectra were scanned from 25-500 amu at 3.09 sec per scan.

(2) High pressure liquid chromatography mass spectra (LC-MS) wereobtained using Finnigan Surveyor HPLC equipped with a quaternary pump, avariable wavelength detector set at 254 nm, XB-C18 column (4.6×50 mm,Sum), and a Finnigan LCQ ion trap mass spectrometer with electrosprayionization. Spectra were scanned from 80-2000 amu using a variable iontime according to the number of ions in the source. The eluents were B:acetonitrile and D: water. Gradient elution from 10% to 90% B in 8 minat a flow rate of 1.0 mL/min is used with a final hold at 90% B of 7min. Total run time is 15 Min.

(3) Routine one-dimensional NMR spectroscopy was performed on 400 MHz or300 MHz Varian Mercury-Plus spectrometers. The samples were dissolved indeuterated solvents obtained from Qingdao Tenglong Weibo Technology Co.,Ltd., and transferred to 5 mm ID NMR tubes. The spectra were acquired at293 K. The chemical shifts were recorded on the ppm scale and werereferenced to the appropriate solvent signals, such as 2.49 ppm forDMSO-d6, 1.93 ppm for CD₃CN, 3.30 ppm for CD₃OD, 5.32 ppm for CD₂Cl₂ and7.26 ppm for CDCl₃ for ¹H spectra.

Example 1

The synthesis of key intermediate D is outlined in FIG. 4, with thedetails of the individual steps given below.

Preparation of (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone(Intermediate A)

To a stirred solution of 5-bromo-2-chlorobenzoic acid (30 g, 0.127 mol)and oxalyl chloride (16.2 g, 0.127 mol) in dichloromethane (200 mL) wasadded DMF (0.5 mL) dropwise. The mixture was stirred at room temperatureovernight and then evaporated to obtain crude product, which was usedfor the next step without further purification. The crude product wasdissolved in dichloromethane (200 mL), the yellow solution was cooled to−5° C., and ethoxybenzene (phenetole) (15.5 g, 0.127 mmol) was added.Then AlCl₃ (17.8 g, 0.134 mmol) was added portionwise over 30 min. Afterthe mixture was stirred at 4° C. for 1 h, TLC showed that no startingmaterial remained. The reaction was quenched by pouring the mixture ontoice, and the suspension was extracted 2× with dichloromethane. Thecombined extracts were washed 2× with 1N HCl, 2× with 1N NaOH, 1× withH₂O and 1× with brine prior to drying over Na₂SO₄. Removal of thevolatiles and recrystallization from absolute ethanol gave intermediateA (25 g, yield 58%).

Preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (IntermediateB)

To a stirred solution of Et₃SiH (6.8 g, 0.058 mol) and(5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone (intermediate A) (10g, 0.029 mol) in TFA (100 mL) was added CF₃SO₃H (0.1 mL). Within minutesthe temperature increased, causing the solution to reflux violently.After slow cooling to room temperature, the mixture was heated to refluxuntil TLC (PE:EA=20:1) showed that no starting material remained. Themixture was evaporated under reduced pressure, the residue was extractedwith ethyl acetate, and the organic layer was separated and washed withwater, aqueous Na₂CO₃, and brine, and dried over Na₂SO₄. Evaporation anddistillation under reduced pressure was performed to eliminate Et₃SiO.Recrystallization of the residue from absolute ethanol gave intermediateB (4.7 g, yield 50%).

Preparation of(3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Intermediate C)

To a stirred solution of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene(intermediate B) (8 g, 24 mmol) in 30 mL of dry THF:toluene (1:2) underAr was added n-BuLi (2.5 M, 0.7 mL) dropwise at −78° C. After stirringfor an additional 30 min, the solution was transferred to a stirredsolution of 2,3,4,6-tetra-O-trimethylsilyl-β-D-glucolactone (also called(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one)(0.28 g, 0.60 mmol) in 30 mL of toluene. The solution was stirred for 1h at −78° C. prior to quenching by addition of 50 mL of methanolcontaining MeSO₃H (1.5 mL, 24 mmol). The mixture was stirred overnight,then quenched by the addition of aqueous NaHCO₃ and extracted withEtOAc. The organic layer was washed with brine and dried over Na₂SO₄.After concentration, the residue was dissolved in hot (50° C.) toluene(20 mL). The resulting solution was poured into 100 mL of stirredhexane. The precipitate was collected by filtration and concentrated togive the crude intermediate, which was used without furtherpurification. The crude intermediate (6 g, 13.6 mmol was dissolved in 40DCM:MeCN (1:1) and Et₃SiH (4.4 mL, 27.3 mmol) was added, followed byaddition of BF₃.Et₂O (2.0 mL, 20.5 mmol) at a rate to insure thetemperature remained under 0° C. The stirred solution was allowed towarm to 0° C. over 5 h. When TLC showed it was complete, the reactionwas quenched by addition of saturated aqueous NaHCO₃. The mixture wasremoved and the residue was extracted with EtOAc. The organic layer waswashed with water and brine and dried over Na₂SO₄. The product wasconcentrated to give intermediate C, which was used without furtherpurification.

Preparation of(3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Intermediate D)

To a stirred solution of(3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Intermediate C) (2 g, 5.9 nmol) in dichloromethane was added BBr₃ (14.6mL, 1 M) dropwise at −78° C. After the addition was complete, themixture was allowed to warm to 0° C. and held at this temperature for 2h. When LC-MS showed that no starting material remained, the mixture wascooled to −78° C. again, and quenched with water. When the temperaturewas stable, saturated NaHCO₃ solution was added. The mixture wasevaporated under reduced pressure, and the residue was extracted withEtOAc. The organic layer was washed with NaHCO₃ and brine, dried overNa₂SO₄, evaporated and purified to obtain intermediate D (0.7 g).

In addition, for use in the synthesis of certain compounds of theinvention, the 2S isomer (intermediate D1) and the 2R isomer(intermediate D2) of intermediate D were separated by preparative LC-MS.Intermediate D1: ¹H NMR (CD₃OD): δ 7.30 (m, 3H), 6.97 (d, 2H, J=6.8 Hz),6.68 (d, 2H, J=6.8 Hz), 4.56 (s, 1H), 4.16 (s, 1H), 3.91˜4.02 (m, 5H),3.79 (m, 1H), 3.64 (m, 1H). Intermediate D2: ¹H NMR (CD₃OD): δ 7.29˜7.33(m, 3H), 7.00 (d, 2H, J=6.8 Hz), 6.70 (d, 2H, J=6.8 Hz), 4.58 (d, 1H,J=4.0 Hz), 3.96˜4.02 (m, 4H), 3.93˜3.95 (m, 1H), 3.81˜3.85 (m, 1H),3.64˜3.69 (m, 1H).

Example 2

The synthesis of compounds E and F within the invention is outlined inFIG. 5, with the details given below.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound E) and(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound F)

To a solution of(3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D) (50 mg, 0.13 mmol) DMF (3.0 mL) were added1-bromo-2-(2-bromoethoxy)ethane (91 mg, 0.39 mmol), Cs₂CO₃ (127 mg, 0.39mmol) and 1-methylpiperazine (66 mg, 0.66 mmol). After being vigorouslystirred at an external temperature of 80° C. overnight, the solution waspurified by preparative HPLC to give compounds E (35 mg) and F (12 mg)as yellow oil. Compound E: ¹H NMR (CD₃OD): δ 7.37-7.27 (m, 3H), 7.13 (d,2H, J=8.4 Hz), 6.84 (d, 2H, J=8.4 Hz), 4.12-4.03 (m, 5H), 3.89-3.67 (m,3H), 3.45-3.38 (m, 3H), 3.32-3.27 (m, 1H), 2.95-2.67 (m, 10H), 2.61 (s,3H); MS ESI (m/z): 551 (M+H)⁺, calc. 550. Compound F: ¹H NMR (CD₃OD): δ7.34-7.29 (m, 3H), 7.11 (d, 2H, J=8.4 Hz), 6.85 (d, 2H, J=8.4 Hz), 4.58(d, 1H, J=3.6 Hz), 4.18-3.93 (m, 7H), 3.82-3.73 (m, 5H), 2.91-2.82 (m,9H); 2.63 (s, 3H).

Example 3

The synthesis of compound G within the invention is outlined in FIG. 6,with the details given below.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2-morpholinoethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound G)

To a solution of(3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D) (50 mg, 0.13 mmol) in DMF (3.0 mL) were added1-bromo-2-(2-bromoethoxy)ethane (91 mg, 0.39 mmol), Cs₂CO₃ (127 mg,(0.39 mmol) and morpholine (68 mg, 0.79 mmol). After being vigorouslystirred at an external temperature of 80° C. overnight, the solution waspurified by preparative HPLC to give compound G (35 mg). ¹H NMR (CD₃OD):δ 7.60-7.40 (m, 3H), 7.12-7.09 (m, 2H), 6.85 (d, 2H, J=8.4 Hz), 4.60 (d,1H, J=3.2 Hz), 4.24-4.11 (m, 4H), 4.09-3.90 (m, 4H), 3.83-3.78 (m, 9H),3.72-3.70 (m, 4H), 3.65-3.64 (m, 2H), 3.04-2.98 (m, 5H); MS ESI (m/z)538 (M+H)⁺, calc. 537.

Example 4

The synthesis of compounds K and L within the invention is outlined inFIG. 7, with the details given below.

Preparation of 4-(5-bromo-2-chlorobenzyl)phenol (Intermediate H)

To a stirred solution of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene(intermediate B) (3.0 g, 9.3 mmol) in dichloromethane (20 mL) was addedBBr3 (1M in dichloromethane, 18.5 mL, 18.5 mmol) under the temperatureof −78° C. The mixture was allowed to warm to room temperature, and thereaction was monitored using TLC (PE:EA=10:1). When TLC showed thereaction was complete, the mixture was poured onto ice and extractedwith dichloromethane. The organic layer was washed with saturated NaHCO₃solution, water, and brine, dried over Na₂SO₄, and evaporated underreduced pressure to obtain intermediate H (2.75 g, yield 90%). ¹H NMR(CDCl₃): δ 7.23˜7.29 (m, 3H), 7.08 (d, 2H, J=8.8 Hz), 6.79 (d, 2H, J=8.8Hz), 4.00 (s, 1H).

Preparation of 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethanol(Intermediate I)

To a stirred solution of 4-(5-bromo-2-chlorobenzyl)phenol (intermediateH) (5.5 g, 18 mmol) in DMF (50 mL) was added Cs₂CO₃ (12 g, 36 mmol).After stirring at room temperature for 0.5 h, 2-bromoethanol (4.6 g, 36mmol) was added dropwise, and the mixture was stirred at 80° C.overnight. The mixture was extracted twice with ethyl acetate, and theorganic layer was washed with water and brine, dried over Na₂SO₄, andevaporated under reduced pressure to obtain intermediate I (4.8 g, yield76%).

Preparation of4-bromo-2-(4-(2-(but-2-ynyloxy)ethoxy)benzyl)-1-chlorobenzene(Intermediate J)

To a stirred solution of 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethanol(intermediate I) (0.5 g, 1.46 mmol) in THF (10 mL) was added NaH (0.084g, 1.76 mmol) at 0° C. degree. The mixture was stirred for 0.5 h, andthen 1-bromobut-2-yne (0.23 g, 1.76 mmol) was added dropsise. Thesolution was stirred at room temperature overnight and then poured overice and extracted with ethyl acetate. The organic layer was washed withwater and brine, dried over Na₂SO₄, concentrated under reduced pressureand purified by column chromatography to obtain intermediate J (0.45yield 78.1%).

Preparation of(2S,3R,4R,5S,6R)-2-(3-(4-(2-(but-2-ynyloxy)ethoxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound K) and(2R,3R,4R,5S,6R)-2-(3-(4-(2-(but-2-ynyloxy)ethoxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound L)

To a −78° C. solution of4-bromo-2-(4-(2-(but-2-ynyloxy)ethoxy)benzyl)-1-chlorobenzene(intermediate J) (0.2 g, 0.50 mmol) in 10 mL of dry THF:toluene (1:2)under Ar was added n-BuLi (2.5 M, 0.22 mL) in hexane. After stirring for30 min following the addition, this solution was transferred to astirred −78° C. solution of2,3,4,6-tetra-O-trimethylsilyl-β-D-glucolactone (also called(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one)(0.28 g, 0.60 mmol) in 10 mL of toluene. The solution was stirred for 2h prior to quenching by addition of 10 ml of MeOH containing MeSO₃H (0.1mL). The mixture was stirred for 30 min, quenched by addition of aqueousNaHCO₃, diluted with 10 mL of H₂O and extracted twice with EtOAc. Thecombined EtOAc fractions were washed with brine, dried over Na₂SO₄,evaporated and used directly for the next step. To a stirred 0° C.solution of the above crude product in CH₂Cl₂ (10 mL) was added Et₃SiH(0.06 g, 1.0 mmol) followed by BF₃.Et₂O (0.1 g, 0.76 mmol). The solutionwas stirred at this temperature for 5 h, quenched by addition ofsaturated aqueous NaHCO₃, and the organic volatiles were removed underreduced pressure. The residue was portioned between 10 mL each of EtOAcand H₂O, and the organic layer was evaporated and purified bypreparative HPLC to obtain compounds K and L. Compound K: ¹H NMR(CD₃OD): δ 7.30˜7.37 (m, 3H), 7.11 (d, 2H, J=8.8 Hz), 6.84 (d, 2H, J=8.8Hz), 4.18˜4.20 (m, 2H), 4.09˜4.11 (m, 3H), 4.03 (d, 2H, J=8 Hz),3.87˜3.90 (m, 3H), 3.82 (m, 1H), 3.39˜3.44 (m, 3H), 3.30 (m, 1H); MS ESIm/z): 477 (M+H)⁺, calc. 476. Compound L: ¹H NMR (CD₃OD): δ 7.31˜7.34 (m,3H), 7.10 (d, 2H, J=8.8 Hz), 6.85 (d, 2H, J=8.8 Hz), 4.58 (d, 1H, J=4Hz), 4.19 (m, 3H), 4.10 (m, 2H), 4.09 (s, 4H), 4.03 (d, 1H, J=4.0 Hz),3.82 (m, 3H), 3.82 (m, 1H).

Example 5

The synthesis of compounds M and N within the invention is outlined inFIG. 8, with the details given below.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound M) and(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound N)

To a stirred solution of(3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D) (200 mg, 0.47 mmol) in DMF (20 mL)was added Cs₂CO₃(0.30 g, 0.94 mmol). The mixture was allowed to stir at room temperaturefor 0.5 h, and then 2-(2-methoxyethoxy)ethyl methanesulfonate (112 mg,0.56 mmol) was added dropwise. The mixture was then stirred at 50° C.overnight, after which the mixture was evaporated and purified bypreparative HPLC to obtain compounds M (17.6 mg) and N (13.9 mg),Compound M: ¹H NMR (CD₃OD): δ 7.31˜7.48 (m, 3H), 7.09 (d, 2H, J=8.8 Hz),6.82 (d, 2H, J=8.8 Hz), 4.06˜4.09 (m, 3H), 4.01 (d, 2H, J=8 Hz),3.79˜3.81 (m, 3H), 3.66˜3.68 (m, 3H), 3.53˜3.56 (m, 2H), 3.39 (m, 3H),3.35 (s, 3H), 3.29 (m, 1H); MS ESI (m/z) 483 (M+H)⁺, calc. 482. CompoundN: ¹H NMR (CD₃OD): δ 7.28˜7.32 (m, 3H), 7.07 (d, 2H, J=8.8 Hz), 6.82 (d,2H, J=8.8 Hz), 4.61 (s, 3H), 4.56 (d, 1H, J=4.0 Hz), 4.16 (m, 1H), 4.07(m, 2H), 3.99 (m, 4H), 3.91 (m, 1H), 3.79 (m, 3H), 3.56 (m, 3H), 3.35(m, 2H), 3.30 (s, 3H).

Example 6

The synthesis of compounds P and Q within the invention is outlined inFIG. 9, with the details given below.

Preparation of 2-(4-(2-(allyloxy)ethoxy)benzyl)-4-bromo-1-chlorobenzene(Intermediate O)

To a stirred solution of 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethanol(intermediate I) (0.5 g, 1.47 mmol) in anhydrous THF was added NaH (84mg, 1.76 mmol) at 0° C. The mixture was stirred at this temperature for30 min, and then allyl bromide (3-bromoprop-1-ene) (0.21 g, 1.75 mmol)was added and the temperature of the mixture was allowed to rise to theroom temperature. The reaction was quenched by pouring it overice-water, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and brine, dried over Na₂SO₄, and thenpurified by column chromatography (EA:PE=1:20 to 1:10) to obtainintermediate O (0.3 g, yield 54%).

Preparation of(2S,3R,4R,5S,6R)-2-(3-(4-(2-(allyloxy)ethoxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound P) and(2R,3R,4R,5S,6R)-2-(3-(4-(2-(allyloxy)ethoxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound Q)

To a stirred solution of2-(4-(2-(allyloxy)ethoxy)benzyl)-4-bromo-1-chlorobenzene (intermediateO) (1.0 g, 2.6 mmol) in 20 mL of dry THF:toluene (1:2) under argon wasadded n-BuLi (2.5 M, 1.1 mL) dropwise at −78° C. After stirring for 30min following the addition, this solution was transferred to a stirredsolution of 2,3,4,6-tetra-O-trimethylsilyl-β-D-glucolactone (also called(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxymethyl)tetrahydro-2H-pyran-2-one) (1.47 g, 3.1 mmol) in 20 mL oftoluene. The solution was stirred for 1 h at −78° C. prior to quenchingby addition of 10 mL of MeOH containing methanesulfonic acid (0.20 mL).The mixture was stirred for 1 h, and then the reaction was quenched byaddition of aqueous NaHCO₃. The mixture was extracted with ethylacetate, and the organic layer was washed with brine, dried over Na₂SO₄and evaporated to obtain the crude product (1.20 g), which was used forthe next step without further purification. To the crude product indichloromethane (20 mL) was added Et₃SiH (0.28 g, 4.8 mmol) followed byaddition of BF₃.Et₂O (0.45 mL, 3.6 mmol) at −5° C. The solution wasallowed to stir at 0° C. for 3 h. When LC-MS revealed the reaction wascomplete, the reaction was quenched by addition of aqueous NaHCO₃ (20mL), the organic volatiles were removed under reduced pressure, and theresidue was partitioned between 20 mL each of EtOAc and H₂O. Afterseparating phases, the organic layer was washed with brine, dried overNa₂SO₄, evaporated and purified by preparative HPLC to obtain compoundsP and Q. Compound P: ¹H NMR (CD₃OD): δ 7.27˜7.36 (m, 3H), 7.10 (d, 2H,J=8.8 Hz), 6.83 (d, 2H, J=8.8 Hz), 5.90 (m, 1H), 5.28˜5.38 (m, 1H),5.17˜5.20 (m, 1H), 4.07˜4.11 (m, 3H), 3.99 (d, 1H, J=8.0 Hz), 3.87 (m,1H), 3.76 (m, 2H), 3.68 (m, 1H), 3.38 (m, 3H), 3.28 (m, 1H); MS ESI(m/z): 465 (M+H)⁺, calc. 464. Compound Q: ¹H NMR (CD₃OD): 7.12˜7.34 (m,3H), 7.09 (d, 2H, J=8.8 Hz), 6.84 (d, 2H, J=8.8 Hz), 5.90 (m, 1H),528˜5.33 (m, 2H), 4.86˜5.20 (m, 2H), 4.58 (d, 1H, J=4.0 Hz), 4.19 (m,1H), 4.01˜4.10 (m, 8H), 3.94 (m, 1H), 3.78 (m, 3H), 3.76 (m, 1H).

Example 7

The synthesis of compounds R and S within the invention is outlined inFIG. 10, with the details given below.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(prop-2-ynyloxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound R) and(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(prop-2-ynyloxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound S)

To a stirred solution of(3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D) (200 mg) in DMF (20 mL) was added Cs₂CO₃ (0.26 g). Themixture was allowed to stir at room temperature for 30 min, and then2-(prop-2-ynyloxy)ethyl methanesulfonate (140 mg) was added dropwise.The mixture was stirred at 60° C. overnight, whereupon LC-MS showedintermediate D was completely consumed. The mixture was filtered,evaporated under reduced pressure, and purified by preparative HPLC togive compounds R (35 mg) and S (20.9 mg). Compound R: ¹H NMR (CD₃OD): δ7.32˜7,35 (m, 3H), 7.10 (d, 2H, J=8.8 Hz), 6.83 (d, 2H, J=8.8 Hz), 4.23(d, 1H, J=2.4 Hz), 4.07˜4.10 (m, 3H), 4.02 (d, 2H, J=8.4 Hz), 3.83˜3.85(m, 3H), 3.65 (m, 1H), 3.35 (m, 3H), 3.32 (s, 1H), 2.86 (t, 1H, J=2.4Hz); MS ESI (m/z): 463 (M+H)⁺, calc. 462. Compound S: ¹H NMR (CD₃OD): δ7.30˜7.33 (m, 3H), 7.09 (d, 2H, J=8.8 Hz), 6.84 (d, 2H, J=8.8 Hz), 4.92(d, 1H, J=4.0 Hz), 4.25 (d, 2H, J=2 Hz), 4.17 (m, 1H), 4.10 (m, 2H),4.00 (m, 4H), 3.92 (m, 1H), 3.85 (m, 3H), 3.81 (m, 1H).

Example 8

The synthesis of compound T within the invention is outlined in FIG. 11,with the details given below.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(1-(prop-2-ynyloxy)propan-2-yloxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound T)

To a stirred solution of(3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D) (50 mg, 0.13 mmol) in DMF (10 mL) was added Cs₂CO₃ (64mg, 0.20 mmol) and the mixture was stirred for 0.5 h. Then1-(prop-2-ynyloxy)propan-2-yl methanesulfonate (38 mg, 0.20 mmol) wasadded, and the mixture was stirred at 40° C. overnight. The mixture thenwas filtered, evaporated under reduced pressure, and the residue waspurified by preparative HPLC to obtain compound T (8.9 mg) as a whitepowder. ¹H NMR (CD₃OD): δ 7.25˜7.34 (m, 3H), 7.08 (d, 2H, J=8.8 Hz),6.82 (d, 2H, J=8.8 Hz), 4.56 (S, 1H), 4.18 (m, 1H), 5.28˜5.33 (m, 2H),4.07 (m, 2H), 4.01 (d, 1H, J=8.0 Hz), 3.87 (d, 1H, 1.2 Hz), 3.85 (m,1H), 3.60 (m, 3H), 3.38 (m, 3H), 3.28 (m, 1H), 2.80 (m, 1H), 1.24 (d,2H).

Example 9

The synthesis of compound V within the invention is outlined in FIG. 12,with the details given below.

Preparation of(2S,3R,4R,5S,6R)-2-(3-(4-(2-(2-aminoethoxy)ethoxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound V)

(3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D) (30 mg, 78.7 mmol),2-(2-(tert-butoxycarbonylamino)ethoxy)ethyl methanesulfonate (26.8 mg,94.5 mmol) and Cs₂CO₃ (30.8 mg, 94.5 mmol) were dissolved in DMF (3 ml)at room temperature and stirred overnight. The mixture was thenextracted with EtOAc, washed with NH₄Cl and NaCl, dried over Na₂SO₄, andevaporated to get the crude product, tert-butyl2-(2-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)ethoxy)ethylcarbamate(intermediate U) (40 mg), which was used for the next step withoutfurther purification. The crude intermediate U was dissolved in MeOH(0.5 mL), MeSO₃H (6 μL) was added, and the mixture was stirred overnightat room temperature. Then the reaction was quenched with NaHCO₃, themixture was extracted with ethyl acetate, and the organic layer waswashed with brine, dried over Na₂SO₄, concentrated, and separated bypreparative HPLC to obtain compound V (11.6 mg). ¹H NMR (CD₃OD): δ7.40˜7.27 (m, 3H), 7.14˜7.10 (m, 2H), 6.87˜6.85 (m, 2H), 4.54 (d, J=16,1H), 4.19˜4.18 (m, 1H), 4.16˜4.14 (m, 2H), 4.05˜4.01 (m, 4H), 3.94˜3.93(m, 1H), 3.88˜3,86 (m, 2H), 3.83˜3.76 (m, 3H), 3.67˜3.57 (m, 1H),3.16˜3.13 (m, 2H); MS ESI (m/z): 468 (M+H)⁺, calc. 467.

Example 10

The synthesis of compound W within the invention is outlined in FIG. 13,with the details given below.

Preparation of4-(4-(2-chloro-5-(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)hut-2-ynylmethanesulfonate (Compound W)

To a solution of(3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D) (30 mg) and but-2-yne-1,4-diyl dimethanesulfonate (16.9mg) in anhydrous DMF (10 mL) was added Cs₂CO₃ (51.5 mg). The mixture wasstirred overnight at room temperature, whereupon LC-MS showed thatintermediate D was exhausted. Then the mixture was poured into water andextracted with EtOAc, washed with water and brine, and dried withanhydrous Na₂SO₄. The solvent was then evaporated under reducedpressure, and the crude product was purified by preparative HPLC toobtain compound W (21.36 mg, yield 51.3%). ¹H NMR (CD₃OD): δ7.32 (m,3H), 7.11 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.93 (t, J=1.2 Hz,2H), 4.81 (t, J=1.2 Hz, 2H), 4.59 (d, J=3.2 Hz, 1H), 4.18 (m, 1H), 4.02(m, 4H), 3.94 (m, 1H), 3.83 (m, 1H), 3.67 (m, 1H), 2.99 (s, 3H); MS ESI(m/z): 527 (M+H)⁺, calc. 526.

Example 11

The synthesis of compounds X and within the invention is outlined inFIG. 14, with the details given below.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(4-hydroxybut-2-ynyloxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound X) and(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-(4-hydroxybut-2-ynyloxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound Y)

To a solution of(3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D) (30 mg) and 4-chlorobut-2-yn-1-ol (16.9 mg) inanhydrous DMF (10 mL) was added K₂CO₃ (51.5 mg). The mixture was stirredovernight at room temperature, whereupon LC-MS showed that intermediateD was exhausted. Then the mixture was poured into water and extractedwith EtOAc, washed with water and brine, and dried with anhydrousNa₂SO₄. The solvent was then evaporated under reduced pressure, and thecrude product was purified by preparative HPLC to obtain compounds X(17.68 mg) and Y (10.32 mg). Compound X: ¹H NMR (CD₃OD): δ 7.32 (m, 3H),7.11 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.71 (t, J=1.2 Hz, 2H),4.19 (t, J=1.2 Hz, 2H), 4.05 (m, 3H), 3.87 (m, 1H), 3.67 (m, 1H), 3.42(m, 3H), 3.27 (m, 1H); MS ESI (m/z): 449 (M+H)⁺, calc. 448. Compound Y:¹H NMR (CD₃OD): δ7.32 (m, 3H), 7.13 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8Hz, 2H), 4.73 (t, J=1.2 Hz, 2H), 4.58 (d, J=4.0 Hz, 1H), 4.20 (t, J=1.2Hz, 2H), 4.18 (m, 1H), 4.02 (m, 4H), 3.94 (m, 1H), 3.82 (m, 1H), 3.66(m, 1H).

Example 12

The synthesis of compounds Z and AA within the invention is outlined inFIG. 15, with the details given below.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(4-methoxybut-2-ynyloxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound Z) and(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-(4-methoxybut-2-ynyloxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound AA)

To a solution of(3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D) (30 mg) and 1-bromo-4-methoxybut-2-yne (30 mg) inanhydrous DMF (10 mL) was added K₂CO₃ (27.1 mg). The mixture was stirredovernight at room temperature, whereupon LC-MS showed that intermediateD was exhausted. Then the mixture was poured into water and extractedwith EtOAc, washed with water and brine, and dried with anhydrousNa₂SO₄. The solvent was then evaporated under reduced pressure, and thecrude product was purified by preparative HPLC to obtain compounds Z(9.68 mg) and AA (5.87 mg). Compound Z: ¹H NMR (CD₃OD): δ 7.30 (m, 3H),7.11 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.73 (t, J=1.2 Hz, 2H),4.58 (d, J=4.0 Hz, 1H), 4.11 (t, J=1.2 Hz, 2H), 4.03 (m, 3H), 3.87 (m,1H), 3.69 (m, 1H), 3.42 (m, 3H), 3.29 (s, 3H); MS ESI (m/z): 463 (M+H)⁺,calc. 462. Compound AA: ¹H NMR (CD₃OD): δ 7.30 (m, 3H), 7.11 (d, J=8.8Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.73 (t, J=1.2 Hz, 2H), 4.57 (s, 2H),4.56 (t, J=1.2 Hz, 1H), 4.17 (m, 1H), 3.87 (m, 1H), 4.11 (m, 2H), 3.92(m, 1H), 3.80 (s, 1H), 3.64 (m, 1H), 3.47 (m, 1H), 3.12 (m, 1H),

Example 13

The synthesis of compound AD within the invention is outlined in FIG.16, with the details given below.

Preparation of 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl4-methylbenzenesulfonate (Intermediate AB)

To a solution of 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethanol(intermediate I) (3.41 g) in anhydrous DCM (20 mL), pyridine (2.0 eq)was added, and then the mixture was stirred and cooled to 0° C. ThenTsCl (1.3 eq) was added in portions, and the mixture was allowed towarmed to room temperature and stirred overnight. TLC (PE:EA=4:1) showedthe reaction was complete. Then the mixture was poured into water andextracted with DCM, washed with water and brine, and dried withanhydrous Na₂SO₄. The solvent was then evaporated under reducedpressure, and the solid crude product was purified by columnchromatography (PE:EA=30:1) to obtain intermediate AB (4.05 g, yield81.7%).

Preparation of4-bromo-1-chloro-2-(4-(2-(cyclopentyloxy)ethoxy)benzyl)benzene(Intermediate AC)

To a solution of cyclopentanol (0.86 g) in anhydrous THF (8.6 mL), NaH(2.0 eq) was added in portions at 0° C., and then the mixture wasstirred at 0° C. for 3 h. Then2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate(intermediate AB) (2.43 g, 0.5 eq) was added in portions. The mixturewas stirred at room temperature overnight, whereupon TLC showed thereaction was complete. Then the reaction mixture was quenched withsaturated NH₄Cl, extracted with EtOAc, washed with water and brine,dried with anhydrous Na₂SO₄, and concentrated to a crude oil. The crudeoil was purified by column chromatography (PE:EA=100:1) to obtain oil AC(1.0 g, yield ˜50%).

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(cyclopentyloxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound AD)

To a solution of 4-bromo-1-chloro-2-(4-(2-(cyclopentyloxy)ethoxy)benzyl)benzene (Intermediate AC) (0.41 g) in anhydrous toluene/THF (v/v=2:1, 10mL), n-BuLi (1.3 eq) was added dropwise at −78° C. and stirred for 1 h.Then the mixture was transferred to a solution of2,3,4,6-tetra-O-trimethylsilyl-β-D-glucolactone (also called(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one)(1.5 eq) in anhydrous toluene (10 mL) at −78° C. The mixture was stirredat −78° C. for 2 h until starting material was consumed. The reactionwas quenched with methanesulfonic acid (0.3 g in 10 mL MeOH), and themixture was allowed to warm to room temperature and stirred overnight.Then 20 mL of water was added. The organic phase was separated, and thewater phase was extracted with EtOAc. The organic phases were combined,washed with saturated NaHCO₃, water and brine, and then dried withanhydrous Na₂SO₄, filtered and concentrated. The residue was purified ona flash column (0.8 g, R_(f)=0.1-0.2, EA:PE=2:1) to collect the crudeproduct. The crude product was dissolved in anhydrous CH₃CN (10 mL),Et₃SiH (1 mL) was added, the mixture was cooled to −5° C., and BF₃.Et₂O(0.6 mL) was added dropwise. Then the reaction was allowed to warm to20° C. and stirred overnight. After the reaction reached completion, itwas quenched with saturated aqueous NaHCO₃. The solvent was removedunder reduced pressure and the residue was extracted with EtOAc andwashed with water and brine. The product was dried with anhydrousNa₂SO₄, filtered, concentrated to a solid, and purified by preparativeHPLC to obtain compound AD as a white powder upon freeze-drying. ¹H NMR(CD₃OD): δ 7.30 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.87 (d, 8.8 Hz, 2H),4.07 (m, 5H), 3.87 (s, 1H), 3.71 (m, 3H), 3.15 (m, 1H), 3.10 (m, 2H),3.07 (m, 6H), 1.72 (m, 6H), 1.55 (m, 2H); MS ESI (m/z): 494 (M+H)⁺,calc. 493.

Example 14

The synthesis of compound AF within the invention is outlined in FIG.17, with the details given below.

Preparation of4-bromo-1-chloro-2-(4-(2-(cyclohexyloxy)ethoxy)benzyl)benzene(Intermediate AE)

To a solution of cyclohexanol (0.76 g, 7.56 mmol) in anhydrous TFIF (10mL), NaH (60%, 0.18 g, 7.56 mmol) was added in portions at 0° C. Themixture was stirred at 0° C. for 0.5 h, and then2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate(intermediate AB) (0.66 g, 1.26 mmol) was added in portions. Then themixture was stirred at room temperature overnight, whereupon TLC showedthe reaction was complete. Then the reaction mixture was quenched withsaturated NH₄Cl, extracted with EtOAc, washed with water and brine,dried with anhydrous Na₂SO₄, and concentrated to a crude oil. The crudeoil was purified by column chromatography (PE:EA=100:1) to obtain oil AE(0.3 g, yield 56.6%). ¹H NMR (400 MHz, CD₃OD): δ 7.28-7.21 (m, 3H), 7.07(d, 2H, J=8.8 Hz), 6.86 (d, 2H, J=8.4 Hz), 4.08 (t, 2H, J=4.8 Hz), 3.98(s, 2H), 3.80 (t, 2H, 4.8 Hz), 3.40-3.20

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(cyclohexyloxy)ethoxy)benzyl)phenyl)-6-(hydroxylmethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound AF)

To a solution of 4-bromo-1-chloro-2-(4-(2-(cyclohexyloxy)ethoxy benzyl)benzene (intermediate AE) (0.3 g, 0.64 mmol) in anhydrous toluene/THF(v/v 2:1, 6 mL), n-BuLi (2.5 N, 0.39 mL, 0.96 mmol) was added dropwiseat −78° C. and stirred for 1 h. Then the mixture was transferred to asolution of 2,3,4,6-tetra-O-trimethylsilyl-β-D-glucolactone (also called(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one)(0.447 g, 0.96 mmol) in anhydrous toluene (5 mL) at −78° C. The mixturewas stirred at −78° C. for 2 h until starting material was consumed. Thereaction was quenched with methanesulfonic acid (0.3 g in 10 mL MeOH),and the mixture was allowed to warm to room temperature and stirredovernight. Then 20 mL of water was added. The organic phase wasseparated, and the water phase was extracted with EtOAc. The organicphases were combined, washed with saturated NaHCO₃, water and brine, andthen dried with anhydrous Na₂SO₄, filtered and concentrated. The residuewas dissolved in anhydrous CH₃CN (4 mL), Et₃SiH (0.2 mL, 1.25 mmol) wasadded and the mixture was cooled to −20° C. Then BF₃.Et₂O (0.12 mL, 0.94mmol) was added dropwise, and the mixture was allowed to warm to 20° C.and stirred overnight. After the reaction reached completion, it wasquenched with saturated aqueous NaHCO₃. The solvent was removed underreduced pressure and the residue was extracted with EtOAc and washedwith water and brine. The product was dried with anhydrous Na₂SO₄,filtered, concentrated to a solid, and purified by preparative HPLC toobtain compound AF as a white powder upon freeze-drying. ¹H NMR (400MHz, CD₃OD): δ 7.37-7.30 (m, 3H), 7.12 (d, 2H, J=8.8 Hz) 6.85 (d, 2H,J=8.8 Hz), 4.11-4.03 (m, 5H), 3.87-3.79 (m, 4H), 3.47-333 (m, 4H);3.32-3.30 (m, 1H), 2.00-1.90 (m, 2H), 1.76-1.75 (m, 2H), 1.60-1.50 (m,1H), 1.33-1.28 (m, 5H); MS ESI (m/z): 508 (M+H)⁺, calc. 507.

Example 5

The synthesis of compound AS within the invention is outlined in FIG.18, with the details given below.

Preparation 5-bromo-2-chlorophenyl)(p-tolyl)methanone (Intermediate AG)

To a stirred suspension of compound 5-bromo-2-chlorobenzoic acid (20 g,85.5 mmol) in 200 mL, of CH₂Cl₂ containing oxalyl chloride (11.2 mL) wasadded 0.5 mL, of DMF. Once the vigorous evolution of gas ceased, thereaction was stirred overnight and then the volatiles were removed underreduced pressure. After dissolving the crude 5-bromo-2-chlorobenzoylchloride in 150 mL of toluene, the solution was cooled to −10° C. ThenAlCl₃ (22.4 g, 170 mmol) was added while insuring the temperature didnot exceed 0° C. HCl gas emission was trapped by passing the gas over astirred concentrated NaOH solution. HPLC-MS revealed the reaction to be98% complete after the addition was finished. The reaction was quenchedby pouring over ice. The suspension was diluted with H₂O and extracted3× with CH₂Cl₂. The combined organic extracts were washed 2× with 1NHCl, 1× with H₂O, 2× with 1M NaOH, and 2× with brine prior to dryingover Na₂SO₄. After removal of the volatiles, crystallization of thecrude product from ethanol (80 mL) yielded intermediate AG (16 g).

Preparation of (5-bromo-2-chlorophenyl)(4-(bromomethyl)phenyl)methanone(Intermediate AH)

To a solution of (5-bromo-2-chlorophenyl)(p-tolyl)methanone(intermediate AG) (16 g, 48.9 mmol) in CCl₄ (80 mL), NBS (10.08 g, 57mmol) and AIBN (0.848 g) was added. Then the mixture was heated to 90°C. After 3 h, CCl₄ was removed under reduced pressure. The residue wasdissolved in CH₂Cl₂ and the solution was washed 1× with HCl (1M) and 2×with brine prior to drying over Na₂SO₄. Solvent was removed underreduced pressure to obtain crude intermediate AH (20.75 g).

Preparation of 4-bromo-2-(4-(bromomethyl)benzyl)-1-chlorobenzene(Intermediate AI)

To a stirred solution of Et₃SiH (17 mL) and(5-bromo-2-chlorophenyl)(4-(bromomethyl)phenyl)methanone (intermediateAH) (20.75 g, 54 mmol) in TFA (100 mL) at 30° C. was added CF₃SO₃H (0.05mL). Within a few minutes the temperature of the solution increasedcausing it to reflux violently. After 3 h, the volatiles were removedunder reduced pressure. The residue was poured into brine and extracted3× with ethyl acetate. The combined organic layers were washed 3× withH₂O, 2× with aqueous Na₂SO₄ and 2× with brine, and dried over Na₂SO₄.The solvent was evaporated under reduced pressure, and the product waspurified by column chromatography to obtain pure intermediate AI (15.5g).

Preparation of 4-(5-bromo-2-chlorobenzyl)benzyl acetate (IntermediateAJ)

To a solution of 4-bromo-2-(4-(bromomethyl)benzyl)-1-chlorobenzene(intermediate AI) (15.5 g) in DNIF (70 mL), NaOAc (16.27 g) was added.The solution was heated to 70° C. After 3 h, H₂O (100 mL) and ethylacetate (200 mL) were added. The organic layer was separated, washedwith brine, and dried over Na₂SO₄. The solvent was evaporated underreduced pressure, and the product was purified by column chromatographyto obtain pure intermediate AJ (8.86 g).

Preparation of (4-(5-bromo-2-chlorobenzyl)phenyl)methanol (IntermediateAK)

To a solution of 4-(5-bromo-2-chlorobenzyl)benzyl acetate (intermediateAJ) (8.86 g) in 60 mL of a mixture of THF:MeOH:H₂O (v/v/v=2:3:1),LiOH.H₂O (2.10 g) was added. The solution was stirred at roomtemperature. After 1 h, H₂O (10 mL) and ethyl acetate (100 mL) wereadded. The aqueous layer was extracted 2× with ethyl acetate. Thecombined ethyl acetate layers were washed with brine and dried overNa₂SO₄. The solvent was evaporated under reduced pressure, and theproduct was purified by column chromatography to obtain pureintermediate AK (6 g).

Preparation of 4-(5-bromo-2-chlorobenzyl)benzaldehyde (Intermediate AL)

To a solution of (4-(5-bromo-2-chlorobenzyl)phenyl)methanol(intermediate AK) (1 g) in CH₂Cl₂ (10 mL), the solution of Dess-Martinperiodinane (DMP) (1.22 g) CH₂Cl₂ (10 mL) was added dropwise. 0° C. Themixture was warmed to room temperature, and the reaction was monitoredby TLC. After 1 h, CH₂Cl₂ was added to dilute the solution and 1 M NaOHwas added to quench the reaction. The CH₂Cl₂ layer was separated andwashed with aqueous NaHSO₃ and brine, and dried over Na₂SO₄. The solventwas evaporated under reduced pressure, and the product was purified bycolumn chromatography to obtain pure intermediate AL (0.62 g).

Preparation of 4-bromo-1-chloro-2-(4-vinylbenzyl)benzene (IntermediateAM)

To a solution of Ph₃PCH₃I (0.97 g) in toluene (5 mL), KN(TMS)₂ (0.5M intoluene, 4.8 mL) was added dropwise at room temperature. After 10 min,the solution of 4-(5-bromo-2-chlorobenzyl)benzaldehyde (intermediate AL)(0.62 g) in toluene (2 mL) was added dropwise. After 2 h, aqueous NaHCO₃was added to quench the reaction, and the resulting mixture wasextracted with ethyl acetate. The organic layers were combined, washedwith brine, and dried over Na₂SO₄. The solvent was evaporated underreduced pressure, and the product was purified by column chromatographyto obtain pure intermediate AM (0.5 g).

Preparation of(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(4-chloro-3-(4-vinylbenzyl)phenyl)tetrahydro-2H-pyran-2-ol(Intermediate AN)

To a solution of 4-bromo-1-chloro-2-(4-vinylbenzyl)benzene (intermediateAM) (215 mg) in toluene:THF (2:1) (3 mL) at −78° C. was added n-BuLi(0.34 mL, 2.5 M in hexane) dropwise. After 45 min, the above mixture wasadded dropwise into a pre-cooled (−78° C.) solution of(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one(453 mg) in toluene (3 mL). After being stirred for 2.5 h at −78° C.,the reaction mixture was quenched by saturated NH₄Cl and diluted withethyl acetate. The organic layer was separated, washed with brine anddried over Na₂SO₄. Concentration gave the crude product which waspurified by chromatography to provide intermediate AN (712 mg) as anoil.

Preparation of(2R,3Z,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-vinylbenzyl)phenyl)tetrahydro-2H-pyran(Intermediate AO)

To a stirred solution of(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(4-chloro-3-(4-vinylbenzyl)phenyl)tetrahydro-2H-pyran-2-ol(intermediate AN) (350 mg) in 4 mL of CH₂Cl₂:CH₃CN (1:1) at −15° C. wasadded Et₃SiH (0.146 mL), followed by BF₃.Et₂O (0.09 mL). During theperiod of addition, the temperature was maintained at approximately −5°C. to −10° C. The stirred solution was allowed to warm to 0° C. over 5h. The reaction was monitored by TLC, and after the starting materialwas consumed, the reaction was quenched by addition of saturated aqueousNaHCO₃. The solvent was removed under reduced pressure. The residue wasthen dissolved in a mixture of 40 mL of ethyl acetate and water (1:1).After separation of the organic layer, the aqueous phase was extracted2× with 20 mL of ethyl acetate. The organic phases were combined andwashed with brine and water before drying over Na₂SO₄. Concentration ofthe solution yielded a yellow gel, which was purified by preparative TLCto obtain pure intermediate AO (100 mg).

Preparation of4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)benzaldehyde(Intermediate AP)

Into a solution of(2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-vinyibenzyl)phenyl)tetrahydro-2H-pyran(intermediate AO) (100 mg) in CH₂Cl₂ (10 mL) at −78° C. was bubbled O₃until the color of the solution turned blue. After TLC showed thestarting material was consumed, a solution of PPh₃ (70 mg) in CH₂Cl₂ (2mL) was added dropwise at −78° C. The solution was then warmed to roomtemperature over a period of 1 h. The precipitate was removed byfiltration, and solvent was removed from the filtrate under reducedpressure. The crude product was purified by preparative TLC to obtainintermediate AP (83 mg). MS ESI (m/z): 770 (M+NH₄)⁺.

Preparation ofN-(4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)cyclopropanamine(Intermediate AQ)

A solution of4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)benzaldehyde(intermediate AP) (40 mg) in CH₂Cl₂:CH₃CN (v/v=1:1) (1.0 mL) was cooledto 0° C., followed by addition of cyclopropylamine (15 mg) and aceticacid (1 mg). After 30 min, NaBH₃CN (17 mg) was added. The reaction wasmonitored by LC-MS. After the starting material was consumed, ethylacetate (20 mL) and water (5 mL) were added to quench the reaction. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate. The organic extracts were combined and washed with brine.Removal of ethyl acetate under reduced pressure and purification of thecrude product by preparative TLC gave intermediate AQ (30 mg). MS ESI(m/z): 794 (M+H)⁺.

Preparation ofN-(4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)-N-cyclopropylacetamide(Intermediate AR)

To a solution of acetic acid (0.11 g) and Et₃N (0.14 mL) in CH₂Cl₂ (1mL) at room temperature, EDCI (96 mg) and HOBt (68 mg) was added. Themixture was stirred 30 min at room temperature. A solution ofN-(4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)cyclopropanamine(intermediate AQ) (40 mg) in CH₂Cl₂ (0.2 mL) was added dropwise. Thereaction was monitored by LC-MS. After the starting material wasconsumed. CH₂Cl₂ was added to dilute the solution. The resulting mixturewas then washed with H₂O, 1N HCl, aqueous NaHCO₃ and brine, CH₂Cl₂ wasremoved under reduced pressure, and the crude product was purified bypreparative TLC to give intermediate AR (20 mg). MS ESI (m/z): 836(M+H)⁺, 853 (M+NH₄)⁺.

Preparation ofN-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)-N-cyclopropylacetamide(Compound AS)

To a solution ofN-(4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)-N-cyclopropylacetamide(intermediate AR) (20 mg) in THF:CH₃OH (v/v=1:1) (4 mL) at roomtemperature was added Pd/C and 1,2-dichlorbenzene (0.05 mL). The mixturewas stirred under H₂. After LC-MS showed the starting material wasconsumed, Pd/C was removed by filtration, and the solvent was removedunder reduced pressure. The crude product was purified by preparativeLC-MS to give compound AS (4 mg). ¹H NMR (400 Hz, CD₃OD): δ 0.77-0.87(4H, m), 2.26 (3H, s), 2.62-2.66 (1H, m), 3.26 (1H, d, J=8.8 Hz),3.36-3.46 (3H, m), 3.66-3.69 (1H, m), 3.86 (1H, d, J=12.8 Hz), 4.02-4.12(3H, m), 4.56 (2H, s), 7.11-7.16 (4H, m), 7.26-7.29 (1H, m), 7.33-7.35(2H, m); MS ESI (m/z): 520 (M+HCO₂)⁻.

Example 16

The synthesis of compounds AV and AW within the invention is outlined inFIG. 19, with the details given below.

Preparation of 3-cyclopropylprop-2-yn-1-ol (Intermediate AT)

Under Ar, n-butyllithium in hexane (3.33 mL, 2.5 M, 8.33 mmol) was addeddropwise to a solution of ethynylcyclopropane (0.5 g, 7.58 mmol) inanhydrous THF (5 mL) at 0° C. The solution was stirred for 1 h after theaddition was completed. To this solution, paraformaldehyde (0.273 g,9.09 mmol) was added. The mixture was stirred for 1 h at 0° C., andallowed to warm to room temperature for another 2 h. The reaction wasgradually quenched with 6N HCl (2 mL) an ice bath. The aqueous layer wasextracted twice with 20 mL of ethyl acetate. The organic layer waswashed with saturated NaHCO₃ solution and water prior to drying overanhydrous Na₂SO₄. The organic phase was concentrated to give crudeintermediate AT (550 mg), which was used in the next step withoutpurification.

Preparation of 3-cyclopropylprop-2-ynyl 4-methylbenzenesulfonate(Intermediate AU)

To a stirred solution of crude 3-cyclopropylprop-2-yn-1-ol (intermediateAT) (0.55 mg) in 10 mL of CH₂Cl₂ was added TsCl (1.33 g, 6.87 mmol) andDMAP (0.035 g, 0.2865 mmol) at 0° C. Triethylamine (0.96 mL, 6.87 mmol)was added dropwise to the mixture and the reaction temperature was heldso as not to exceed 0° C. After stirring for 3 h, the mixture wasquenched with 10 mL of water. The aqueous layer was extracted twice with20 mL each of CH₂Cl₂. The organic layer was washed with 20% HCl andwater prior to drying over anhydrous Na₂SO₄. The organic phase wasconcentrated and the crude product was purified by gel columnchromatography to obtain intermediate AU (0.4 g).

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(3-cyclopropylprop-2-ynyloxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound AV)

To a stirred solution of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D1) (20 mg, 0.0526 mmol) in 1 mL of DMF was added Cs₂CO₃(21 ng, 0.063 mmol) and 3-cyclopropylprop-2-ynyl methylbenzenesulfonate(intermediate AU) (20 mg, 0.079 mmol) at room temperature. Afterstirring for 2 h, the reaction was quenched with 1 mL of ice water. Themixture was extracted 3× with ethyl acetate (5 each). The combinedorganic layers were washed 2× with water (5 mL each) and brine prior todrying over Na₂SO₄. Concentration of the solution and purification ofthe crude product by preparative LC-MS afforded compound AV (10 mg). ¹H.NMR (CD₃OD): δ 7.37˜7.34 (2H, m), 7.30˜7.28 (1H, dd, J=8.8, 2 Hz),7.13˜7.11 (2H, d, J=8.8 Hz), 6.87˜6.83 (2H, d, J=8.8 Hz), 4.61 (2H, d,J=2 Hz), 4.11 (1H, d, J=9.2 Hz), 4.10˜4.04 (2H, dd, J=23.6, 14.8 Hz),3.90˜3.87 (1H, m), 3.72˜3.68 (1H, m), 3.49˜3.39 (3H, m), 3.31˜3.28 (1H,m), 1.31˜1.24 (1H, m), 0.79˜0.75 (2H, m), 0.62˜0.59 (2H, m).

Preparation of(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-(3-cyclopropylprop-2-ynyloxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound AW)

Compound AW was prepared by reaction of(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D2) with 3-cyclopropylprop-2-ynyl 4-methylbenzenesulfonate(intermediate AU) in the presence of Cs₂CO₃ using the same procedure asdescribed above for compound AV. ¹H NMR (CD₃OD): δ 7.34˜7.30 (3H, m),7.11˜7.08 (2H, d, J=8.8 Hz), 6.86˜6.84 (2H, d, J=8.8 Hz), 4.61 (2H, d,J=1.6 Hz), 4.58 (1H, d, J=4 Hz), 4.19˜4.17 (1H, m), 4.03˜4.00 (4H, m),3.94˜3.93 (1H, q), 3.84˜3.80 (1H, m), 3.68˜3.64 (1H, q), 1.29˜1.24 (1H,m), 0.78˜0.75 (2H, m), 0.62˜0.59 (2H, m).

Example 17

The synthesis of compound BE within the invention is outlined in FIG.20, with the details given below.

Preparation of(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-acetylbenzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (Intermediate AY)

To a stirred solution of(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethylbenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (intermediate AX) (10 g, 10.83 mmol) (prepared by methodsanalogous to those described in US20040138439) AcOH (130 mL) at 120° C.was added K₂CrO₇ (6.3 g, 21.42 mmol) in one portion. The mixture wasstirred for 22 h at the same temperature. Volatiles were removed underreduced pressure, AcOEt was added, and the solids were removed byfiltration. The organic layer was washed with a saturated solution ofNaHCO₃ and brine prior to drying over Na₂SO₄. Concentration of theorganic solution and purification of the resulting residue by silicalgel column (PE:EA=3:1) provided intermediate AY (2.3 g).

Preparation of(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(prop-1-en-2-yl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (Intermediate AZ)

To a solution of Ph₃PMeI (378 mg, 0.935 mmol) in toluene (3 mL) wasadded KN(TMS)₂ (0.5 M, 1.8 mL) dropwise. After stirring for 40 min,(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-acetylbenzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (intermediate AV) (360 mg, 0.626 mmol) in toluene (5 mL) wasadded. After stirring overnight, the reaction was quenched with asaturated solution of NaHCO₃. The mixture was extracted 3× with AcOEt.The combined organic extracts were washed 1× with brine prior to dryingover Na₂SO₄. Concentration of the solution gave an oily residue, whichwas redissolved in 3 of CH₂Cl₂, and then 0.2 mL of pyridine (2.47 mmol),0.23 mL of Ac₂O (2.44 mmol) and DMAP (catalytic quantity) were added.The mixture was stirred for 2 h at room temperature. Additional CH₂Cl₂(20 mL) was added, the mixture was washed 2× with 1N HCl and 1× withbrine prior to drying over Na₂SO₄. Concentration of the solution andpurification of the crude product by silical gel column gaveintermediate AZ (286 mg).

Preparation of(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-(3-bromoprop-1-en-2-yl)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (Intermediate BA)

A mixture of(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(prop-1-en-2-yl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (intermediate AZ) (236 mg, 0.412 mmol) and NBS (110 mg, 0.618mmol) in chlorobenzene (5 mL) was stirred at 135° C. for 2 h. The solidswere filtered and washed with AcOEt. The organic portion was washed 1×with H₂O and 1× with brine prior to drying over Na₂SO₄. Concentrationand purification of the resulting residue by preparative TLC gaveintermediate AZ (144 mg).

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(3-methoxyprop-1-en-2-yl)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Intermediate BB)

The solution of(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-(3-bromoprop-1-en-2-yl)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (intermediate BA) (110 mg, 0.169 mmol and 4 mL 0.3M NaOMe inMeOH (freshly-distilled) was stirred at 70° C. for 2.5 h. Then thereaction was quenched with H₂O. After removing the volatiles, theaqueous layer was extracted 3× with AcOEt. The organic portion waswashed I X with a saturated solution of NH₄Cl and 1× with brine prior todrying over Na₂SO₄. Concentration and purification of the crude productby preparative TLC gave intermediate BA (48 mg).

Preparation of(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(3-methoxyprop-1-en-2-yl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (Intermediate BC)

To a solution of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(3-methoxyprop-1-en-2-yl)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate BB) (48 mg, 0.11 mmol) in CH₂Cl₂ (1 mL) was added pyridine(0.1 mL, 1.06 mmol) followed by Ac₂O (0.09 mL, 1.11 mmol) and DMAP(catalytic quantity) added in one portion. The mixture was stirredovernight at room temperature. Then 20 mL CH₂Cl₂ was added, and themixture was washed 2× with 1N HCl and 1× with brine prior to drying overNa₂SO₄. Concentration and purification of the crude product bypreparative TLC afforded intermediate BC (32 mg).

Preparation of(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(1-(methoxymethyl)cyclopropyl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (Intermediate BD)

To a cooled (0° C.) solution of ZnEt₂ (0.16 mL, 0.16 mmol) CH₂Cl₂ (0.4mL) was added a solution of TEA (12 μL, 0.16 mmol) in CH₂Cl₂ (0.2 mL).After stirring for 20 min, a solution of CH₂I₂ (43 mg, 0.16 mmol) inCH₂Cl₂ (0.2 mL) was added. After stirring for an additional 20 min, asolution of(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(3-methoxyprop-1-en-2-yl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (intermediate BC) (32 mg, 0.053 mmol) in CH₂Cl₂ (0.4 mL) wasadded. The mixture was stirred overnight prior to quenching with asaturated solution of NaHCO₃. The mixture was extracted 3× with CH₂Cl₂,and the organic portion was washed with brine prior to drying overNa₂SO₄. Concentration of the solution gave crude intermediate BC (25mg).

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(1-(methoxymethyl)cyclopropyl)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound BE)

To a solution of the above crude(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(1-(methoxymethyl)cyclopropyl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (intermediate BD) (25 mg) in THF:MeOH:H₂O (2:3:1) (1 mL) wasadded LiOH.H₂O (4.66 mg). After stirring for about 2.5 h, the volatileswere removed with a rotary evaporator. The residue was taken up withwater (5 mL) and AcOEt (20 mL), the organic layer was separated, and theaqueous layer was extracted 3× with AcOEt. The combined organic phasewas washed 1× with brine prior to drying over Na₂SO₄. Concentration andpurification of the crude product by preparative HPLC afforded compoundBE (7.5 mg). ¹H NMR (CD₃OD, 400 MHz) δ 7.35-7.33 (m, 2H), 7.27 (dd, 8.0,2.0 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 4.11-4.01(m, 3H), 3.87 (d, 9.6 Hz, 1H), 3.70-3.66 (m, 1H), 3.48 (s, 2H),3.45-3.34 (m, 4H), 3.26 (s, 3H), 0.83-0.82 (m, 4H); MS ESI (m/z): 449(M+H)⁺, 466 (M+NH₄)⁺, 493 (M+HCO₂)⁻.

Example 18

The synthesis of compound BN within the invention is outlined in FIG.21, with the details given below. The structures of compoundssynthesized in this example were confirmed using the followingprocedures: ¹H NMR data were acquired on a Varian Mercury 300spectrometer at 300 MHz, with chemical shifts referenced to internalTMS. Liquid chromatography electrospray ionization mass spectrometry(LC-ESI-MS) analysis was performed on instrumentation consisting ofShimadzu LC-10AD vp series FIPLC pumps and dual wavelength UV detector,a Gilson 215 autosampler, Sedex 75c evaporative light scattering (ELS)detector, and a PE/Sciex API 150EX mass spectrometer. The ELS detectorwas set to a temperature of 40° C., again setting of 7, and a N₂pressure of 3.3 atm. The Turbo Ion Spray source was employed on the API150 with an ion spray voltage of 5 kV, a temperature of 300° C., andorifice and ring voltages of 5 V and 175 V respectively. Positive ionswere scanned in Q1 from 160 to 650 m/z. 5.0 μL injections were performedfor each sample, on a Phenomenex Gemini 5 μm C18 column. Mobile phasesconsisted of 0.05% formic acid in both HPLC grade water (A) and HPLCgrade acetonitrile (B) using the following gradients with a flow rate of2 mL/min: 0.00 min, 95% A, 5% B; 4.00 min, 0% A,

Preparation of 4-(5-bromo-2-chlorobenzoyl)phenethyl acetate(Intermediate BF)

To a solution of commercially available 5-bromo-2-chlorobenzoic acid (5g, 21.23 mmol) in 30 of anhydrous DCM was added a catalytic amount ofDMF followed by oxalyl chloride (1.95 mL, 22.3 mmol) and stirred for 2 hat room temperature. A mixture of aluminum trichloride (3.68 g, 27.6mmol) and phenethyl acetate (3.38 mL, 21.23 mmol) in 15 mL DCM wascooled in an ice-bath and the acid chloride was transferred to it usinga canula. The mixture was stirred at room temperature for 4 h. Themixture was poured into 100 mL of ice-cold water and the organic layerwas isolated. The aqueous solution was extracted with 25 mL DCM. Thecombined organic solution was washed with brine (25 mL) and dried(Na₂SO₄), filtered and evaporated. Purification on silica gel using anISCO column with 5:1 hexane:EtOAc followed by 10:1 hexane:EtOAc gaveintermediate BF (2.1 g, yield 26%). ¹H NMR (300 MHz, CDCl₃): δ 8.12 (d,J=2.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.56 (d,J=8.4 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz,1H), 4.31 (t, J=6.9, 6.6 Hz, 2H), 3.01 (t, J=6.9, 6.6 Hz, 2H), 2.04 (s,3H).

Preparation of 4-(5-bromo-2-chlorobenzyl)phenethyl acetate (intermediateBG)

A mixture of 4-(5-bromo-2-chlorobenzoyl)phenethyl acetate (intermediateBF) (1 g, 2.62 mmol), borontrifluoride diethylether (0.65 mL, 10.4 mmol)and triethylsilane (0.84 mL, 10.4 mmol) was heated at 85° C. for 2 h ina sealed tube. The reaction vessel was cooled to room temperature andice-water (50 mL) was added. The product was extracted with ethylacetate (2×25 mL), washed with brine (25 mL), dried (Na₂SO₄), filteredand evaporated. Purification on silica gel using an ISCO column with 5%ethyl acetate in hexane gave intermediate BG (620 mg, yield 65%). ¹H NMR(300 MHz, CDCl₃): δ 7.27-7.10 (m, 7H), 4.27 (t, J=6.9, 7.2 Hz, 2H), 4.03(s, 2H), 2.92 (t, J=6.9, 7.2 Hz, 2H), 2.05 (s, 3H.

Preparation of 2-(4-(5-bromo-2-chlorobenzyl)phenyl)ethanol (IntermediateBH)

4-(5-bromo-2-chlorobenzyl)phenethyl acetate (intermediate BG) (400 mg,1.09 mmol) and potassium carbonate (481 mg, 3.48 mmol) were stirred atroom temperature in a mixture of 3 mL methyl alcohol and 0.5 mL waterfor 3 h. Solvents were evaporated and the residue taken up in 25 mLether was washed with water (5 mL) and brine (20 mL), dried (Na₂SO₄),filtered and evaporated. Purification on silica gel using an ISCO columnwith 15:1 hexane:EtOAc gave intermediate BH (271 mg, yield 76%). ¹H NMR(300 MHz, CDCl₃): δ 7.27-7.07 (m, 7H), 4.02 (s, 2H), 3.84 (m, 2H), 2.86(m, 3H); LC-ESI-MS (m/z): 325 (M+H).

Preparation of 2-(4-(2-(allyloxy)ethyl)benzyl)-4-bromo-1-chlorobenzene(Intermediate BI)

A mixture of 2-(4-(5-bromo-2-chlorobenzyl)phenyl)ethanol (intermediateBH) (245 mg, 0.75 mmol), allyl bromide (2.6 mL, 3.01 mmol), potassiumhydroxide (84 mg, 1.5 mmol) and tetra-n-butylammonium iodide (13.9 mg,0.037 mmol) was stirred at room temperature for 6 h. Water (1 mL) wasadded and extracted with chloroform (3×1 mL), washed with brine (1 mL)and dried (Na₂SO₄), filtered and evaporated. Preparative TLC using 10:1hexane:EtOAc gave intermediate BI (246 mg, yield 89%), ¹H NMR (300 MHz,CDCl₃): δ 7.26-7.08 (m, 7H), 5.90 (m, 1H), 5.22 (m, 2H), 4.02 (s, 2H),3.99 (m, 2H), 3.64 (t, J=6.9, 7.2 Hz, 2H), 2.89 (t, J=6.9, 7.2 Hz, 2H).

Preparation of(2S,3R,4S,5R,6R)-2-(3-(4-(2-(allyloxy)ethyl)benzyl)-4-chlorophenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-methoxytetrahydro-2H-pyran(Intermediate BJ)

To a mixture of 2-(4-(2-(allyloxy)ethyl)benzyl)-4-bromo-1-chlorobenzene(intermediate BI) (123 mg, 0.34 mmol) and(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one(362 mg, 0.67 mmol) in anhydrous THF (1.5 mL) under argon and kept at−78° C. was added dropwise a 1.6 M solution of n-butyl lithium in hexane(0.63 mL) over 15 min. The mixture was stirred at −78° C. for 1.5 h. Asolution of methanesulfonic acid (0.1 mL) in methanol (1 mL) was addedto the reaction mixture and allowed to warm to room temperature overtime. The mixture was stirred at room temperature for 21 h. A saturatedsolution of sodium bicarbonate was slowly added to the reaction mixtureto bring the pH to 8. Water (2 mL) was added and the product wasextracted into ethyl acetate (3×2 mL), the combined ethyl acetatesolution was washed with brine (1.5 mL), dried (Na₂SO₄), filtered andevaporated. Preparative thin layer chromatography (TLC) using 12:1hexane:EtOAc gave intermediate BJ (80 mg, yield 28%). LC-ESI-MS (m/z):807 (M-OMe).

Preparation of(2S,3S,4R,5R,6R)-2-(3-(4-(2-(allyloxy)ethyl)benzyl)-4-chlorophenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran(Intermediate BK)

(2S,3R,4S,5R,6R)-2-(3-(4-(2-(allyloxy)ethyl)benzyl)-4-chlorophenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-methoxytetrahydro-2H-pyran(intermediate BJ) (55 mg, 0.065 mmol) was taken up in 1 mL anhydrous DCMkept under argon, and triethylsilane (31.4 μL, 0.197 mmol) was added.The mixture was brought to −20° C. and borontrifluoride diethyletherate(20.1 μL, 0.164 mmol) was added. The mixture was allowed to warm andstirred at −5° C. to 0° C. for 3 h. Water (0.5 mL) was added to quenchthe reaction and the organic layer was separated. The aqueous layer wasextracted with DCM (1 mL), and the combined organic solution was washedwith brine (1 mL), dried (Na₂SO₄), filtered and evaporated. PreparativeTLC using 10:1 hexane:EtOAc gave intermediate BK (39.5 mg, yield 60%).¹H NMR (300 MHz, CDCl₃): δ 7.30-7.03 (m, 27H), 5.90 (m, 1H), 5.22 (m,2H), 4.88-4.70 (m, 3H), 4.65-4.38 (m, 5H), 4.16-4.08 (m, 3H), 4.05-3.88(m, 4H), 3.82-3.72 (m, 5H), 3.60-3.52 (m, 3H); LC-ESI-MS (m/z): 808(M+H).

Preparation of2-(4-(2-chloro-5-(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)ethanol(Intermediate BL)

(2S,3S,4R,5R,6R)-2-(3-(4-(2-(allyloxy)ethyl)benzyl)-4-chlorophenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran(intermediate BK) (50 mg, 0.061 mmol) was taken up in 90% aqueous aceticacid (1 mL), and sodium acetate (30.4 mg, 0.37 mmol) was added, followedby palladium (II) chloride (27.4 mg, 0.154 mmol). The mixture was heatedat 70° C. for 5 h. Solvent was evaporated and the residue was taken upin 2 mL DCM and the mixture was filtered through a short Celite® pad.The pad was washed with a copious amount of DCM until all material hadeluted. After evaporation of solvent, the residue was purified by TLCusing 4:1 hexane:EtOAc to obtain intermediate BL (20 mg, yield 42%).LC-ESI-MS (m/z): 770 (M+H), 791 (M+H+Na).

Preparation of(2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-(2-(difluoromethoxy)ethyl)benzyl)phenyl)tetrahydro-2H-pyran(Intermediate BM)

To a mixture of2-(4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)ethanol(intermediate BL) (20 mg, 0.020 mmol) and sodium sulfate (0.40 mg, 0.003mmol) in anhydrous acetonitrile (0.5 mL) kept at 45° C. was added2,2-difluoro-2-(fluorosulfonyl)acetic acid (4.63 mg, 2.7 μL, 0.026mmol). The mixture was stirred at this temp for 1 h and poured into 3 mLwater. Product was extracted into ether (3×1 mL), dried (Na₂SO₄) andevaporated. The residue was purified by TLC using 6:1 hexane:EtOAc toobtain intermediate BM (7 mg, yield 33%).

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(difluoromethoxy)ethyl)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound RN)

(2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-(2-(difluoromethoxy)ethyl)benzyl)phenyl)tetrahydro-2H-pyran(intermediate BM) was taken up in a mixture of 4:1methanol:tetrahydrofuran (0.5 mL) and 9.6 μL of 1,2-dichlorobenzene wasadded followed by palladium on charcoal (10%, 5 mg). The mixture wasstirred at room temperature under a hydrogen balloon for 30 min. Themixture was passed through a short Celite® pad to remove the catalyst,and the pad was washed with methanol (1 mL). Solvent was evaporated andthe product was purified by TLC using 8:1 dichloromethane:methanol toobtain compound BN (2.5 mg, yield 64%). ¹H NMR (300 MHz, CDCl₃): δ7-33-7.11 (m, 7H), 6.30 (t, J_(C-F)=75.6 Hz, 1H), 4.13 (d, J=9 Hz, 1H),4.04 (m, 4H), 3.86-3.80 (m, 3H), 3.64 (t, J=4.5, 6.6 Hz, 2H), 3.47-3.41(m, 2H), 2.90 (t, J=6.9, 7.2 Hz, 2H); LC-ESI-MS (m/z): 457 (M−H).

Example 19

The synthesis of compound BQ within the invention is given below.

Preparation of 2-cyclopropoxyethanol (Intermediate BO)

To a suspension of Mg powder (0.87 g, 36.1 mmol) and iodine (catalytic)in THF (4 mL) was added slowly BrCH₂CH₂Br (4.6 g, 24.5 mmol) THF (8 mL).The exothermic reaction was cooled in an ice-bath. After completeaddition of BrCH₂CH₂Br, a solution of 2-(2-bromoethyl)-1,3-dioxolane (1g, 5.6 mmol) was added dropwise. The reaction mixture was then kept atreflux for 24 h, quenched by addition of aqueous NH₄Cl, and extractedwith DCM. The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated to give crude intermediate BO (400 mg) asyellow oil.

Preparation of 2-cyclopropoxyethyl 4-methylbenzenesulfonate(Intermediate BP)

To a solution of 2-cyclopropoxyethanol (400 mg, 3.92 mmol) DCM (10 mL)were added TsCl (821 mg, 4.31 mmol) and Et₃N (0.6 mL, 4.31 mmol). Thereaction was stirred at room temperature overnight. Then, 1N HCl wasadded, and the reaction was extracted with DCM. The combined organiclayers were washed with brine, dried over Na₂SO₄, and concentrated togive a yellow oil. The oil was purified by preparative TLC to obtainintermediate BP (50 mg) as a yellow oil.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound BQ)

To a solution of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D1) (30 mg, 0.08 mmol) in anhydrous DMF (1 mL) were added2-cyclopropoxyethyl 4-methylbenzenesulfonate (intermediate BP) (20 mg,0.08 mmol) and Cs₂CO₃ (52 mg, 0.16 mmol). The mixture was stirred atroom temperature for 12 h. Then the reaction mixture was poured intowater, extracted with EA, washed with brine, dried with anhydrous Na₂SO₄and concentrated to an oil. The oil was purified by preparative HPLC toobtain compound BQ (11 mg as a colorless oil. ¹H NMR (CD₃OD): δ 7.30 (m,3H), 7.11 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 4.13 (m, 5H), 3.85(m, 3H), 3.81 (m, 1H), 3.40 (m, 4H), 3.30 (m, 1H), 0.52 (m, 4H); MS ESI(m/z) 465 (M+H)⁺, calc. 464,

Example 20

The synthesis of compound BT within the invention is given below.

Preparation of 2-(2,2,2-trifluoroethoxy)ethanol (Intermediate BR)

2,2,2-trifluoroethanol (15 g), 1,3-dioxolan-2-one (19.8 g) and Et₃N (15g) were mixed together, and then the mixture was heated to 100° C. andstirred for 24 h. Then the reaction mixture was distilled to obtainintermediate BR (12.7 g).

Preparation of 2-(2,2,2-trifluoroethoxy)ethyl 4-methylbenzenesulfonate(Intermediate BS)

2-(2,2,2-trifluoroethoxy)ethanol (intermediate BR) (12.7 g) wasdissolved in anhydrous pyridine, then TsCl (1.3 eq) was added, and themixture was stirred at room temperature for 16 h, after which TLC showedthe reaction was complete. Then the mixture was poured into water,extracted with EA, washed with water and brine, and dried with anhydrousNa₂SO₄. The solvent was removed and the residue purified by columnchromatography to obtain intermediate BS (0.3 g).

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2,2,2-trifluoroethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound BT)

To(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D1) (200 mg) in anhydrous DMF were added2-(2,2,2-trifluoroethoxy)ethyl 4-methylbenzenesulfonate (intermediateBS) (1.5 eq) and Cs₂CO₃ (2 eq). The mixture was stirred at roomtemperature for 12 h, after which LC-MS showed the reaction wascomplete. The reaction mixture was poured into water, extracted with EA,washed with water and brine, and then dried with anhydrous Na₂SO₄ andconcentrated to an oil. The oil was purified by preparative-HPLC toobtain compound BT (117 mg). ¹H NMR (CD₃OD, 400 MHz): δ 7.32 (m, 3H),7.11 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.62 (s, 2H), 4.08˜4.12(m, 3H), 4.02˜4.05 (m, 3H), 4.00˜3.94 (m, 2H), 3.90˜3.87 (m, 1H),3.72˜3.68 (m, 1H), 3.46˜3.39 (m, 3H), 3.30˜3.27 (m, 1H); MS ESI (m/z)507 (M+H)⁺, calc. 506.

Example 21

The synthesis of compound BW within the invention is give below.

Preparation of 2-(cyclohex-2-enyloxy)ethanol (Intermediate BU)

To a solution of 3-bromocyclohex-1-ene (0.5 g) in anhydrous DMF (5 mL)were added ethylene glycol (3 eq) and Cs₂CO₃ (5 g). The mixture washeated to 80° C. and stirred overnight, after which TLC (PE:EA=20:1)showed the reaction was complete. Then the mixture was poured into waterand extracted with EA, washed with water and brine, and concentrated toan oil, which was purified by column chromatography to obtainintermediate BU (0.3 g).

Preparation of 2-(cyclohex-2-enyloxy)ethyl-4-methylbenzenesulfonate(Intermediate BV)

To 2-(cyclohex-2-enyloxy)ethanol (intermediate BU) (0.3 g) in anhydrouspyridine was added TsCl (1.3 eq). The mixture was stirred at roomtemperature for 16 h, after which TLC showed the reaction was complete.The mixture was poured into water, extracted with EA, washed with waterand brine, and dried with anhydrous Na₂SO₄. Solvent was removed and theresidue purified by column chromatography to obtain intermediate BV (0.3g).

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(cyclohex-2-enyloxy)ethoxy)henzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound BW)

To(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D1) (30 mg) in anhydrous DMF were added2-(cyclohex-2-enyloxy)ethyl 4-methylbenzenesulfonate (intermediate BV)(1.5 eq) and Cs₂CO₃ (2 eq). The mixture was stirred at room temperaturefor 16 h, after which LC-MS showed the reaction was complete. Thereaction mixture was poured into water, extracted with EA, washed withwater and brine, and then dried with anhydrous Na₂SO₄ and concentratedto an oil. The crude oil was purified by preparative-HPLC to obtaincompound BW (17.1 mg). ¹H NMR (CD₃OD, 400 MHz): δ 7.32 (m, 3H), 7.11 (d,J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.87˜5.76 (s, 2H), 4.59 (s, 1H),4.11˜3.89 (m, 6H), 3.89˜3.76 (m, 3H), 3.72˜3.68 (m, 1H), 3.49˜3.40 (m,3H), 2.03˜1.98 (m, 2H), 1.89˜1.84 (m, 1H), 1.80˜1.62 (m, 2H), 1.79˜1.51(m, 1H); MS ESI (m/z) 506 (M+H)⁺, calc. 505.

Example 22

The synthesis of compound BZ within the invention is given below.

Preparation of (E)-3-cyclopropylprop-2-en-1-ol (Intermediate BX)

To a solution of 3-cyclopropylprop-2-yn-1-ol (intermediate AT) (1 g,0.0096 mol, purity 92%) in 10 ml of dry ether was added carefully asuspension of LiAlH₄ (0.79 g, 0.021 mol) in dry ether (10 ml) at 0° C.The resulting solution was stirred at room temperature for 3.5 h, andthen quenched with 20 ml of ice-water. The aqueous layer was extracted3×10 ml of ether, and the combined organic layers were washed withsaturated NH₄Cl and brine, dried over anhydrous Na₂SO₄, and concentratedto obtain intermediate BX (0.75 g, purity 62%, yield 79.8%) as a crudeyellow oil, which was used in the next step without furtherpurification.

Preparation of (E)-(3-bromoprop-1-enyl)cyclopropane (Intermediate BY)

To a solution of (E)-3-cyclopropylprop-2-en-1-ol (intermediate BX)(0.375 g, 2.37 mmol, purity 62%) in dry diethyl ether (4 ml) was addedphosphorus tribromide (0.36 ml, 3.83 mmol) at 0° C. After being stirredat the same temperature for 2 h, the mixture was warmed to roomtemperature and stirred for another 2 h. The reaction mixture was pouredinto ice water, and the aqueous layer was extracted 3× with 10 ml ofether. The combined organic layers were washed with water and brine,dried over anhydrous Na₂SO₄, and concentrated to obtain intermediate BY(0.15 g) as a crude yellow oil, which was used in the next step withoutfurther purification.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((E)-3-cyclopropylallyloxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2,1-pyran-3,4,5-triol(Compound BZ)

To a stirred solution of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D1) (37 mg, 0.097 mmol) in 1.5 ml of DMF was added Cs₂CO₃(48 mg, 0.146 mmol) and (E)-(3-bromoprop-1-enyl)cyclopropane(intermediate BY) (50 mg) at room temperature. After stirring for 3 h,the reaction was quenched with 2 ml of ice water. The mixture wasextracted 3× with ethyl acetate (5 ml), and the combined organic layerswere washed 2× with water (5 ad) and brine, dried over Na₂SO₄,concentrated, and purified by preparative LC-MS to obtain compound BZ(8.6 mg). ¹H NMR (CD₃OD, 400 MHz): δ 7.37˜7.33 (2H, m), 7.30˜7.27 (1H,dd, J=8.2, 2 Hz), 7.11˜7.09 (2H, d, J=8.8 Hz), 6.82˜6.79 (2H, d, J=8.8Hz), 5.77˜5.70 (1H, dt, J=15.2, 6 Hz), 5.39˜5.33 (1H, dd, J=15.2, 8.8Hz), 4.43˜4.41 (2H, dd, J=6.4, 1.0 Hz), 4.10 (1H, d, J=9.6 Hz),4.08˜3.98 (2H, dd, J=23.6, 15.2 Hz), 3.90˜3.87 (1H, m), 3.72˜3.67 (1H,m), 3.49˜3.39 (3H, m), 3.31˜3.27 (1H, m), 1.47˜1.45 (1H, m), 0.76˜0.71(2H, m), 0.41˜0.37 (2H, m); MS ESI (m/z) 461 (M+H)⁺, calc. 460.

Example 23

The synthesis of compound CC within the invention is outlined in FIG.22, with the details given below. The structures of compoundssynthesized in this example were confirmed using the analyticalprocedures as described in Example 18.

Preparation of 2-(2-fluoroethoxy)ethanol (Intermediate CA)

2-Fluoroethanol (5.0 g, 78 mmol), triethylamine (8.4 g, 83 mmol), andtetrabutylammonium bromide (0.50 g, 1.5 mmol) were combined and stirredat ambient temperature for 5 min. Ethylene carbonate (7.6 g, 86 mmol)was added and the resulting mixture was heated at 100° C. for 18 h,Preliminary distillation of the reaction mixture at atmospheric pressurewas performed to remove low boiling point liquids. Subsequentdistillation of the mixture under high vacuum was performed to obtainthe title compound (1.2 g, 14%) as a clear oil. The temperature of thedistillation head was 110-115° C. when the product was being collectedunder high vacuum. ¹H NMR (CDCl₃, 300 MHz): δ 4.52 (dt, 2H, J1=64.0 Hz,J2=5.2 Hz), 3.75-3.55 (m, 6H), 3.16 (br s, 1H).

Preparation of 2-(2-fluoroethoxy)ethyl 4-methylbenzenesulfonate(Intermediate CB)

2-(2-Fluoroethoxy)ethanol (0.11 g, 1.0 mmol), p-toluenesulfonyl chloride(0.19 g, 1.0 mmol), and DMAP (0.12 g, 1.0 mmol) were dissolved indichloromethane (2 ml) at 0° C. The resulting mixture was stirred for 2h at 0° C., after which it was subjected directly to silica gelchromatography using dichloromethane as the eluent to give the titlecompound (70 mg, 27%) as a clear oil. It was observed that the size ofthe column affects reaction yield, with a smaller column giving a betteryield. ¹H NMR (CDCl₃, 300 MHz): δ 7.79 (d, 2H, J=11.6 Hz), 7.33 (d, 2H,J=11.6 Hz), 4.48 (dt, 2H, J1=64.0 Hz, J2=5.6 Hz), 4.17 (t, 2H, J=6.4Hz), 3.71 (t, 2H, J=6.4 Hz), 3.66 (dt, 2H, J1=5.6 Hz, J2=39.2 Hz), 2.44(br S, 3H).

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2-fluoroethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound CC)

2-(2-fluoroethoxy)ethyl 4-methylbenzenesulfonate (52 mg, 0.19 mmol)dissolved in anhydrous DMF (3 mL) was added to a flask containing(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D1) (57 mg, 0.15 mmol) in DMF (3 mL) at room temperature.Cesium carbonate (0.12 g, 0.36 mmol) was added to the flask, and theresulting mixture was stirred at room temperature for 48 hr. Thereaction mixture was diluted with diethyl ether (50 mL) and the organiclayer was washed with aqueous solutions of ammonium chloride (50 mL),sodium bicarbonate (50 mL), and NaCl (50 mL), followed by drying oversodium sulfate. The organic layer was concentrated in vacuo, followed bypreparative TLC using 15% methanol in dichloromethane as the mobilephase to yield the title compound (4.5 mg, 5.0%). NMR (CDCl₃, 300 MHz):δ 7.30 (d, 1H, J=11.6 Hz), 7.17-7.12 (br m, 2H), 7.04 (d, 2H, J=11.6Hz), 6.78 (d, 2H, J=11.6 Hz), 4.52 (dt, 2H, J1=5.6 Hz, J2=63.6 Hz), 4.33(br s, 1H), 4.13 (br s, 1H), 4.04-3.96 (m, 4H), 3.81-3.67 (m, 5H),3.63-3.49 (m, 2H), 3.38-3.21 (m, 3H), 2.78 (br s, 1H), 1.77 (br s, 2H);LC/MS: theoretical mass=470.15; observed M+1=471.6, M+Na=493.4).

Example 24

The synthesis of compound CF within the invention is outlined in FIG.23, with the details given below. The structures of compoundssynthesized in this example were confirmed using the analyticalprocedures as described in Example 18.

Preparation of (Intermediate CD)

2,2-Difluoroethanol (5.1 g, 63 mmol), triethylamine (6.7 g, 66 mmol),and tetrabutylammonium bromide (0.40 g, 1.3 mmol) were mixed for 5 minat ambient temperature. Ethylene carbonate (6.1 g, 69 mmol) was addedand the combined mixture was refluxed at 100° C. for 18 h. Distillationat atmospheric pressure was first conducted to strip off low boilingpoint liquids. Then distillation was performed under high vacuum toyield the title compound as a clear oil (4.7 g, 59%). The temperature ofthe distillation head was 109-113° C. when the title compound was beingcollected under high vacuum. ¹H NMR (CDCl₃, 300 MHz): δ 5.86 (ttd, 1H,J1=73.6 Hz, J2=5.6 Hz, J3=0.8 Hz), 3.74-3.61 (m, 6H), 2.65 (br s, 1H).

Preparation of 2-(2,2-difluoroethoxy)ethyl 4-methylbenzenesulfonate(Intermediate CE)

2-(2,2-difluoroethoxy)ethanol (0.13 g, 1.0 mmol), p-toluenesulfonylchloride (0.19 g, 1.0 mmol), and DMAP (0.12 g, 1.0 mmol) were dissolvedin dichloromethane (2 ml) at 0° C. and stirred for 2 h at thistemperature. The reaction mixture was loaded onto a small column, whichwas eluted with dichloromethane to yield the title compound as a clearoil (53 mg, 19%). It was observed that the size of the column affectsreaction yield, with a smaller column giving a better yield. ¹H NMR(CDCl₃, 300 MHz): δ 7.78 (d, 2H, J=11.2 Hz), 7.34 (d, 2H, J=11.2 Hz),5.76 (tt, 1H, J1=5.6 Hz, J2=73.6 Hz), 4.17 (t, 2H, J=6.0 Hz), 3.75 (t,2H, J=6.0 Hz), 3.64 (td, 2H, J=6.0 Hz, J2=20 Hz), 2.45 (br s, 3H).

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2,2-difluoroethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound CF)

2-(2,2-difluoroethoxy)ethyl 4-methylbenzenesulfonate (53 mg, 0.19 mmol)dissolved in anhydrous DMF (3 mL) was added to a reaction flaskcontaining(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D1) (57 mg, 0.15 mmol) in DMF (3 mL) at room temperature.Cesium carbonate (98 mg, 0.30 mmol) was added to the flask, and theresulting mixture was stirred for 48 fir at room temperature. Thereaction was diluted with diethyl ether (50 mL) and the organic layerwas washed with an aqueous solution of ammonium chloride (50 mL), sodiumbicarbonate (50 mL), and NaCl (50 ml), after which it was dried oversodium sulfate, filtered and concentrated en vacuo. The residue waspurified by preparative TLC using 15% methanol in dichloromethane as themobile phase to yield the title compound (4.6 mg, 5.0%). ¹H NMR (CDCl₃,300 MHz): □δ 7.33 (d, 1H, J=11.2 Hz), 7.15 (d, 1H, J=11.2 Hz), 7.14 (s,1H), 7.06 (d, 2H, J=11.6 Hz), 6.79 (d, 2H, J=11.6 Hz), 5.86 (tt, 1H,J1=5.2 Hz, J2=66.4 Hz), 4.07-3.98 (m, 3H), 3.87-3.84 (m, 3H), 3.84-3.71(m, 2H), 3.74 (td, 2H, J1=5.6 Hz, J2=18.4 Hz), 3.66-3.54 (m, 3H),3.30-3.36 (m, 2H), 2.78 (br s, 1H), 2.42 (br s, 1H), 1.65 (s, 2H);LC/MS: theoretical mass=488.14; observed M+1=489.2, M+Na=511.4).

Example 25

The synthesis of compound CH within the invention is outlined in FIG.24, with the details given below.

Preparation of(2S,3R,4R,5S,6R)-2-(3-(4-(2-(2-bromoethoxy)ethoxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate CC)

To a stirred suspension of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D1) (100 mg, 0.26 mmol) in N,N-dimethylformamide (3 mL)and cesium carbonate (162 mg, 0.52 mmol) was added1-bromo-2-(2-bromoethoxy)ethane (182 mg, 0.79 mmol). The mixture wasstirred overnight at room temperature. The solution was diluted withwater and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were concentrated under reduced pressure. Theresidue was purified by preparative TLC to give 30 mg of yellow oil (21%yield), which was used in the next step without purification.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2-(pyrrolidin-1-yl)ethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound CH)

To a stirred suspension of(2R,3R,4R,5S,6R)-2-(3-(4-(2-(2-bromoethoxy)ethoxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(20 mg, 0.04 mmol) in N,N-dimethylformamide (5 mL) and cesium carbonate(25 mg, 0.08 mmol) was added pyrrolidine (26 mg, 0.38 mmol). The mixturewas stirred for 5 h at 50° C. The solution was diluted with water andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were concentrated under reduced pressure. The residue waspurified by preparative HPLC to give 15 mg of white solid (76% yield;HPLC purity: 99%). HPLC retention time: 1.85 min; Waters 2695Separations Module equipped with a Waters 2996 Photodiode Array Detectorand a Waters Micromass ZQ Detector; Waters XTerra. C18 3.5 μm, 20 mm×2.1mm column, 1.0 mL/min, detection at 190˜400 nm; 1.7 min gradient 10-50%A, followed by 1.8 min gradient 50-95% A, hold 1 min at 95% A; solventA: 0.045% formic acid in acetonitrile; solvent B: 0.1% formic acid inMilli-Q water. ¹H NMR (CD₃OD, 400 MHz): δ 7.28-7.36 (m, 3H), 7.12-7.14(d, dr 8.8 Hz, 2H), 6.84-6.86 (d, J=8.8 Hz, 2H), 4.15-4.17 (m, 2H),4.00-4.14 (m, 2H), 3.68-3.72 (m, 1H), 3.23-3.48 (m, 6H), 2.01-2.03 (m,5H), 1.34-1.30 (m, 2H); MS ES⁻ (m/z): 566 (M+45)⁻.

Example 26

The synthesis of compound CK within the invention is outlined in FIG.25, with the details given below,

Preparation of(S)-3-(2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethoxy)tetrahydrofuran(Intermediate CI)

To a stirred solution of (R)-tetrahydrofuran-3-ol (320 mg, 3.63 mmol) indry tetrahydrofuran (10 mL) was added sodium hydride (145 mg, 3.63 mmol,60%) slowly under 0° C. The reaction was stirred at this temperature for30 min and then 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl4-methylbenzenesulfonate (intermediate AB) (300 mg, 0.61 mmol was added.The reaction was warmed to room temperature and then heated to refluxovernight. The reaction was quenched with saturated ammonium chlorideand extracted with ethyl acetate. The organic layer was washed withbrine, dried over sodium sulfate and concentrated to a yellow oil. Thecrude oil was purified by flash chromatography to get 200 mg ofcolorless oil (80% yield).

Preparation of(3R,4S,5S,6R)-2-(4-chloro-3-(4-(2-((S)-tetrahydrofuran-3-yloxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol(Intermediate CJ)

To a −65° C. solution of (S)-3-(2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethoxy)tetrahydrofuran (200 mg, 0.49 mmol) in anhydroustoluene/tetrahydrofuran (6 ml v/v=2:1) was added dropwise n-butyllithum(2.5 M in hexane, 0.3 mL), and the pale yellow mixture was stirred for30 min at −65° C. The mixture was transferred to a −65° C. solution of(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one(280 mg, 0.73 mmol) in toluene (4 mL). The mixture was stirred at −65°C. for 2 h until starting material was consumed. The reaction wasquenched with methanesulfonic acid (0.04 mL, 1.7 mmol) in methanol (6mL), and the mixture was allowed to warm to 20° C. and stirredovernight. The reaction was quenched with saturated sodium bicarbonate.The organic phase was separated, and the aqueous phase was extractedwith ethyl acetate. The organic phases were combined, washed withsaturated sodium bicarbonate, then with water and then with brine priorto drying over anhydrous sodium sulfate. Removal of volatiles afforded200 mg of crude solid product, which was used in the next step withoutfurther purification.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-((S)-tetrahydrofuran-3-yloxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound CK)

To a −15° C. solution of crude product from the previous step (200 mg,0.38 mmol) in 1:1 anhydrous acetonitrile/dichloromethane (4 mL) wasadded triethylsilane (0.12 mL, 0.76 mmol). Boron trifluoride diethyletherate (0.08 mL, 0.57 mmol) was added dropwise, and then the mixturewas stirred for 4 h at −10° C. The reaction was quenched with saturatedaqueous sodium bicarbonate. The volatiles were removed under reducedpressure, and the residue was extracted with ethyl acetate, washed withwater and then with brine. The residue was dried over anhydrous sodiumsulfate, filtered and concentrated to a solid, which was purified bypreparative HPLC-MS give 12 mg pure product HPLC purity: 99%). HPLCretention time: 2.2 min; Waters 2695 Separations Module equipped with aWaters 2996 Photodiode Array Detector and a Waters Micromass ZQDetector; Waters XTerra C18 3.5 μm, 20 mm×2.1 mm column, 1.0 mL/min,detection at 190˜400 nm; 1.7 min gradient 10-50% A, followed by 1.8 mingradient 50-95% A, hold 1 min at 95% A; solvent A: 0.045% formic acid inacetonitrile; solvent B: 0.1% formic acid in Milli-Q water. ¹H NMR(CD₃OD, 400 MHz): δ 7.28-7.36 (m, 3H), 7.11-7.13 (d, J=8.0 Hz, 2H),6.83-6.85 (d, J=8.4 Hz, 2H), 4.26 (s, 1H), 4.03-4.25 (m, 5H), 3.71-3.89(m, 8H), 3.32-3.34 (m, 3H), 3.27-3.32 (m, 1H), 2.02-2.05 (m, 2H); MS ES⁻(m/z): 539 (M+45)⁻.

Example 27

The synthesis of compound CM within the invention is given below.

Preparation of 4-bromo-1-chloro-2-(4-(2-cyclobutoxyethoxy)benzyl)benzene(Intermediate CL)

To a solution of cyclobutanol (260 mg, 3.6 mmol) in anhydroustetrahydrofuran (4 mL) was added sodium hydride (138 mg, 5.7 mmol) inportions at 0° C. The mixture was stirred at 0° C. for 30 min, and then2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate(intermediate AB) (300 mg, 0.6 mmol) was added in portions. The mixturewas refluxed for 3 h, whereupon TLC showed the reaction was complete.The reaction mixture was quenched with saturated ammonium chloride,extracted with ethyl acetate, washed with water and then with brine,dried over anhydrous sodium sulfate, and concentrated to a crude oil.The crude oil was purified by column chromatography (PE:EA=10:1) to getintermediate CL as an oil product (117 mg, yield: ˜49%).

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclobutoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound CM)

To a solution of4-bromo-1-chloro-2-(4-(2-cyclobutoxyethoxy)benzyl)benzene (0.10 mg, 0.3mmol) in anhydrous toluene/tetrahydrofuran (v/v=2/1, 2 mL) was addedn-BuLi (0.17 mL, 2.5 M) dropwise at −78° C. The mixture was stirred for30 min and then transferred to a solution of(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one(195 mg, 0.4 mmol) in anhydrous toluene (1 mL) at −78° C. The mixturewas stirred at −78° C. for 2 h until starting material was consumed. Thereaction was quenched with methanesulfonic acid (54 μL in 1.4 mLmethanol), and the mixture was allowed to warm to room temperature andstirred overnight. Then water was added, the organic phase wasseparated, and the water phase was extracted with ethyl acetate. Theorganic phases were combined, washed with saturated sodium bicarbonate,then with water and then with brine, and then dried over anhydroussodium sulfate, filtered and concentrated to get the crude product. Thecrude product was dissolved in acetonitrile/dichloromethane (1.2 mL),triethylsilane (0.3 mL, 1.9 mmol) was added, the mixture was cooled to−40° C., and boron trifluoride diethyl etherate (1.8 μL, 1.4 mmol) wasadded quickly. After addition, the mixture was stirred for 2 h at 0° C.The reaction was quenched with saturated aqueous sodium bicarbonate. Thevolatiles were removed under reduced pressure and the residue wasextracted with ethyl acetate, washed with water and then with brine, andthen dried over anhydrous sodium sulfate. The residue was filtered,concentrated, and purified by preparative LC-MS to obtain 16 mg of pureproduct. ¹H NMR (CD₃OD, 400 MHz): δ 7.25-7.34 (m, 3H), 7.09-7.11 (m,2H), 6.81-6.83 (m, 2H), 4.01-4.09 (m, 6H), 3.85-3.88 (m, 1H), 3.65-3.70(m, 3H), 3.37-3.44 (m, 3H), 3.26-3.28 (m, 1H), 2.18-2.23 (m, 2H),1.90-1.95 (m, 2H), 1.55-1.72 (m, 1H), 1.48-1.53 (m, 1H); MS ES⁻ (m/z):523 (M+45)⁻; MS ES⁺ (m/z): 479 (M+1)⁺, 496 (M+18)⁺.

Example 28

The synthesis of compound CP within the invention is outlined in FIG.26, with the details given below.

Preparation of 2-(1-methylcyclopropoxy)ethanol (Intermediate CN)

To Mg powder (250 mg, 10.25 mmol) suspended in THF (10 mL) was slowlyadded 1,2-dibromoethane (0.7 mL) over 3 h via funnel to maintain gentlereflux. After an additional 1 h, when the mixture had cooled to below46° C., 2-(2-bromoethyl)-2-methyl-1,3-dioxolane (1 g, 5.1 mmol) wasslowly added over 1 h to maintain the temperature below 46° C. Anadditional portion of THF (5 mL) was added, and the mixture was stirredovernight at 40˜46° C. The reaction was quenched by addition to ammoniumchloride at 0° C., and the mixture was stirred for 2 h before it wastransferred to an extractor and separated. The organic layer wasconcentrated under vacuum, and the aqueous layer was extracted withdichloromethane (20 mL×2). The combined organic layers were washed withbrine and concentrated to obtain crude product as a yellow oil (0.32 g,crude), which was used in the next step without further purification.

Preparation of 2-(1-methylcyclopropoxy)ethyl 4-methylbenzenesulfonate(Intermediate CO)

To the crude 2-(1-methylcyclopropoxy)ethanol from the previous step(0.32 g) in a mixture of 4.6N sodium hydroxide (6.3 mL, 2.52 mmol) andtetrahydrofuran (3 mL) was added 4-methylbenzene-1-sulfonyl chloride(2.1 g, 11.2 mmol) dichloromethane (6 mL) at 0-5° C. The solution wasstirred for 3 h at 0-5° C., and then extracted with dichloromethane. Theorganic layer was washed with brine, dried over sodium sulfate, andconcentrated to obtain crude product (100 mg), which was used in thenext step without further purification.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(1-methylcyclopropoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound GP)

To a stirred suspension of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(intermediate D1) (140 mg, 0.26 mmol) in N,N-dimethylformamide (2 mL)and cesium carbonate (130 mg, 0.4 mmol) was added2-(1-methylcyclopropoxy)ethyl 4-methylbenzenesulfonate (54 mg, 0.20mmol). The mixture was stirred overnight at 50° C. The solution wasdiluted with water and the aqueous layer was extracted with ethylacetate. The combined organic layers were concentrated under reducedpressure, and the residue was purified by preparative HPLC-MS to give 30mg of white solid (31% yield; HPLC purity 97.5%). HPLC retention time:3.27 min; Waters 2695 Separations Module equipped with a Waters 2996Photodiode Array Detector and a Waters Micromass ZQ Detector; WatersXTerra C18 5 μm, 50 mm×2.1 mm column; 1.0 mL/min, detection at 190˜400nm; 6 min gradient 10-95% A, hold 8 min at 95% A; solvent A: 0.045%formic acid in acetonitrile, solvent B: 0.1% formic acid in Milli-Qwater. ¹H NMR (CD₃OD, 400 MHz): δ 7.28-7.36 (m, 3H), 7.12-7.14 (d, J=8.8Hz, 2H), 6.83-6.86 (d, J=8.8 Hz, 2H), 4.64 (s, 1H), 4.02-4.12 (m, 5H),3.81-3.91 (m, 3H), 3.71-3.73 (m, 1H), 3.28-3.48 (m, 5H), 1.42 (s, 3H),0.81-0.83 (d, J=5.6 Hz, 2H), 0.44-0.46 (m, 2H); MS ES⁻ (m/z): 523(M+45)⁻.

Example 29

The synthesis of compound CT within the invention is outlined in FIG.27, with the details given below.

Preparation of 4-bromo-1-chloro-2-(4-(2-(vinyloxy)ethyl)benzyl)benzene(Intermediate CQ)

To a solution of 2-(4-(5-bromo-2-chlorobenzyl)phenyl)ethanol(intermediate BH) (500 mg, 1.46 mmol), [IrCl(cod)]₂ (9.8 mg, 0.015 mmol)and sodium carbonate (93 mg, 0.87 mmol) in toluene (2 mL) was addedvinyl acetate (0.27 mL, 2.91 mmol) under argon. The reaction mixture washeated to 100° C. and stirred for 2 h. The solution was allowed to coolto room temperature, and then diluted with 50 mL of ethyl acetate. Themixture was washed with water (20 mL) and then with brine (20 mL), anddried over sodium sulfate. The residue was concentrated and purified bycolumn chromatography (eluent EA:PE:Et₃N=1:20:0.01) to provide 445 mg ofyellow solid. ¹H-NMR (CDCl₃, 400 MHz): δ 7.22˜7.14 (m, 3H), 7.10 (d,2H), 7.04 (d, 2H), 6.40 (dd, J=14.4 and 6.8 Hz, 1H), 4.11 (dd, J=14.4and 2.0 Hz, 1H), 3.96 (s, 2H), 3.93 (dd, J=6.8 and 2.0 Hz, 1H), 3.82 (t,J=7.2 Hz, 2H), 2.88 (t, J=7.2 Hz, 2H).

Preparation of 4-bromo-1-chloro-2-(4-(2-cyclopropoxyethyl)benzyl)benzene(Intermediate CR)

To a stirred mixture of4-bromo-1-chloro-2-(4-(2-(vinyloxy)ethyl)benzyl)benzene (100 mg, 0.27mmol) and Et₂Zn (0.68 mL, 0.68 mmol, 1.0 M in hexane) in dry ethyl ether(2 mL) was added diiodomethane (0.06 mL, 0.68 mmol) dropwise during 20min at room temperature under argon. After stirring overnight, thereaction mixture was poured slowly into ice cold dilute hydrochloridesolution with stirring. The mixture was extracted with ethyl acetate(3×10 mL). The combined organic layers were washed with water (10 mL)and then with brine (10 mL), and then dried over sodium sulfate. Theresidue was concentrated and purified by preparative TLC (eluentEA:PE=1:25) to obtain intermediate CR (86 mg) as a light yellow oil.¹H-NMR (CDCl₃, 400 MHz): δ 7.32˜7.24 (m, 3H), 7.18 (d, 2H), 7.12 (d,2H), 4.05 (s, 2H), 3.73 (t, J=7.2 Hz, 2H), 3.32˜3.29 (m, 1H), 2.88 (t,J=7.2 Hz, 2H), 0.57˜0.44 (m, 4H).

Preparation of(3R,4S,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethyl)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol(Intermediate CS)

To a solution of4-bromo-1-chloro-2-(4-(2-cyclopropoxyethyl)benzyl)benzene (105 mg, 0.29mmol) in anhydrous toluene/THF (1.2 mL, v/v=2:1) was added dropwisen-BuLi (2.5 M in hexane, 0.14 mL) at −65° C., and the mixture wasstirred for 30 min at −65° C. Then a −65° C. solution of(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one(148 mg, 0.32 mmol) in toluene (1.2 mL) was added dropwise over 15 min.The mixture was stirred at −65° C. for 3 h until starting material wasconsumed. The reaction was quenched with methanesulfonic acid (0.04 mL,0.60 mmol) in methanol (1 mL), and the mixture was allowed to warm toroom temperature and stirred overnight. The reaction was quenched withsaturated sodium bicarbonate, the organic phase was separated and theaqueous phase was extracted with ethyl acetate. The combined organicphases were washed with saturated bicarbonate, then with water, and thenwith brine, and dried over sodium sulfate. Removal of the volatilesafforded a residue (134 mg), which was used in the next step withoutfurther purification.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethyl)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound CT)

To a −15° C. solution of crude product from the previous step (134 mg,0.28 mmol) in anhydrous acetonitrile/dichloromethane (2 mL, 1:1) wasadded triethylsilane (0.18 mL, 1.12 mmol). Then BF₃.Et₂O (0.11 mL, 0.84mmol) was added dropwise, and the mixture was stirred for 3 h at −15° C.The reaction was quenched with saturated aqueous bicarbonate and thevolatiles were removed under reduced pressure. The residue was extractedwith ethyl acetate, washed with water, then with brine, and dried oversodium sulfate. The sample was concentrated and purified by preparativeHPLC-MS to give 42 mg of white solid. ¹H NMR (CD₃OD, 400 MHz): δ7.37˜7.28 (m, 3H), 7.12 (s, 4H), 4.11 (d, J=9.2 Hz, 1H), 4.13˜4.03 (dd,J=24.4 and 14.8 Hz, 2H), 3.88 (d, J=14.4 Hz, 1H), 3.72˜3.68 (m, 3H),3.48˜3.39 (m, 3H), 3.32˜3.28 (m, 2H), 2.80 (t, J=6.8 Hz, 2H), 0.47˜0.44(m, 4H); MS ESI (m/z): 449 [M+H]⁺, calc. 448.

Example 30

The synthesis of compound CX within the invention is outlined in FIG.28, with the details given below.

Preparation of 4-bromo-1-chloro-2-(4-(vinyloxymethyl)benzyl)benzene(Intermediate CU)

To a solution of (4-(5-bromo-2-chlorobenzyl)phenyl)methanol(intermediate AK) (1.5 g, 4.81 mmol), [IrCl(cod)]₂ (31 mg, 0.046 mmol)and sodium carbonate (0.29 g, 2.73 mmol) in toluene (6 mL) was addedvinyl acetate (0.84 mL, 9.10 mmol) under argon. The reaction mixture washeated to 100° C. and stirred for 4 h. The solution was allowed to coolto room temperature, and then diluted with 50 mL of ethyl acetate. Themixture was washed with water (20 mL) and then with brine (20 mL), anddried over sodium sulfate. The residue was concentrated and purified bycolumn chromatography (eluent EA:PE:Et₃N=1:30:0.01) to provide 1.09 g ofwhite solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.36˜7.28 (m, 5H), 7.22 (d, 2H),6.61 (dd, J=14.4 and 6.8 Hz, 1H), 4.78 (s, 2H), 4.37˜4.33 (dd, J=14.4and 2.4 Hz, 1H), 4.14˜4.12 (dd, J=6.8 and 2.4 Hz, 1H), 4.09 (s, 2H).

Preparation of 4-bromo-1-chloro-2-(4-(cyclopropoxymethyl)benzyl)benzene(intermediate CV)

To a stirred mixture of4-bromo-1-chloro-2-(4-(vinyloxymethyl)benzyl)benzene (0.7 g, 2.07 mmol)and Et₂Zn (5.18 mL, 5.18 mmol, 1.0 M in hexane) in dry ethyl ether (10mL) was added diiodomethane (0.42 mL, 5.18 mmol) dropwise during 20 minat room temperature under argon. After stirring overnight, the reactionmixture was poured slowly into ice cold dilute hydrochloride solutionwith stirring. The mixture was extracted with ethyl acetate (3×20 mL).The combined organic layers were washed with water (20 mL) and then withbrine (20 mL), and then dried over sodium sulfate. The residue wasconcentrated and purified by column chromatography (eluent EA:PE=1:200)to obtain intermediate CV (0.6 g) as a colorless oil. ¹H NMR (CDCl₃, 400MHz): δ 7.33˜7.24 (m, 5H), 7.18 (d, 2H), 4.55 (s, 2H), 4.07 (s, 2H),3.40˜3.37 (m, 1H), 0.69˜0.49 (m, 4H).

Preparation of(3R,4S,5S,6R)-2-(4-chloro-3-(4-(cyclopropoxymethyl)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol(Intermediate CW)

To a solution of4-bromo-1-chloro-2-(4-(2-cyclopropoxymethyl)benzyl)benzene (0.6 g, 1.71mmol) in anhydrous toluene/THF (6 mL, v/v=2:1) was added dropwise n-BuLi(2.5 M in hexane, 0.82 mL) at −65° C., and the mixture was stirred for30 min at −65° C. Then a −65° C. solution of(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one(0.87 g, 1.88 mmol) in toluene (6 mL) was added dropwise over 15 min.The mixture was stirred at −65° C. for 3.5 h until starting material wasconsumed. The reaction was quenched with methanesulfonic acid (0.23 mL,3.58 mmol) in methanol (6 mL), and the mixture was allowed to warm toroom temperature and stirred overnight. The reaction was quenched withsaturated sodium bicarbonate, the organic phase was separated and theaqueous phase was extracted with ethyl acetate. The combined organicphases were washed with saturated bicarbonate, then with water, and thenwith brine, and dried over sodium sulfate. Removal of the volatilesafforded a residue (0.75 g), which was used in the next step withoutfurther purification.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(cyclopropoxymethyl)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound CX)

To a −15° C. solution of crude product from the previous step (0.75 g,1.61 mmol) anhydrous acetonitrile/dichloromethane (6 mL, 1:1) was addedtriethylsilane (1.01 mL, 6.42 mmol). Then BF₃.Et₂O (0.61 mL, 4.81 mmol)was added dropwise, and the mixture was stirred fir 3 h at −15° C. Thereaction was quenched with saturated aqueous bicarbonate and thevolatiles were removed under reduced pressure. The residue was extractedwith ethyl acetate, washed with water, then with brine, and dried oversodium sulfate. The sample was concentrated and purified by preparativeHPLC-MS to give 0.35 g of white solid. ¹H NMR (CD₃OD, 400 MHz):7.38˜7.30 (m, 3H), 7.25 (d, 2H), 7.19 (d, 2H), 4.52 (s, 2H), 4.13˜4.07(m, 3H), 3.91˜3.88 (m, 1H), 3.73˜3.68 (m, 1H), 3.49˜3.35 (m, 4H),3.32˜3.28 (m, 1H), 0.61˜0.47 (m, 4H); MS ESI (m/z): 435 [M+H]⁺, calc.434.

Example 31

The synthesis of compound DC within the invention is given below,

Preparation of 1-(4-(5-bromo-2-chlorobenzyl)phenoxy)propan-2-ol(Intermediate CY)

To a solution of 4-(5-bromo-2-chlorobenzyl)phenol (intermediate H) (3 g,10.1 mmol) and cesium carbonate (6.6 g, 20.1 mmol) inN,N-dimethylacetamide (30 mL), 1-bromopropan-2-ol (2.8 g, 20.1 mmol) wasadded. The solution was heated to 80° C. and stirred overnight. Then thereaction mixture was cooled to room temperature, diluted with water,extracted with ethyl acetate, washed with sodium ammonium chloride andthen with brine, and dried over sodium sulfate. The residue wasconcentrated and purified by column chromatography to intermediate CY(2.95 g, yield: 82%), ¹H NMR (CDCl₃, 400 MHz): δ 7.24-7.32 (m, 3H),7.12-7.14 (m, 2H), 6.87-6.89 (m, 2H), 4.20-4.24 (m, 1H), 4.02 (s, 2H),3.94-3.97 (m, 1H), 3.78-3.82 (m, 1H), 1.29-1.31 (m, 3H).

Preparation of4-bromo-1-chloro-2-(4-(2-(1-ethoxyethoxy)propoxy)benzyl)benzene(Intermediate CZ)

To a solution of 1-(4-(5-bromo-2-chlorobenzyl)phenoxy)propan-2-ol (857mg, 2.4 mmol) in dichloromethane (20 mL) was added ethyl vinyl ether(1.2 mL, 12 mmol) and pyridinium p-toluenesulfonate (24 mg), and themixture was stirred at room temperature for 2 h, whereupon startingmaterial had been completely consumed as determined by TLC (eluentPE:EA=1:1). Solid sodium bicarbonate (5 g) was added, and the mixturewas stirred for 10 min. Water (25 mL) was added, and the mixture wasextracted with ethyl acetate, washed with sodium chloride, and driedover sodium sulfate. The residue was concentrated and purified by columnchromatography to obtain intermediate CZ (900 mg, yield 87%) as a yellowoil. ¹H NMR (CDCl₃, 400 MHz): δ 7.23-7.30 (m, 3H), 7.09-7.11 (m, 2H),6.85-6.87 (m, 2H), 4.86-4.94 (m, 1H), 4.10-413 (m, 1H), 4.00 (s, 2H),3.84-3.99 (m, 1H), 3.69-3.72 (m, 1H), 3.50-3.59 (m, 1H), 1.19-1.37 (m,9H).

Preparation of 4-bromo-1-chloro-2-(4-(2-(vinyloxy)propoxy)benzyl)benzene(Intermediate DA)

To a solution of4-bromo-1-chloro-2-(4-(2-(1-ethoxyethoxy)propoxy)benzyl)-benzene (550mg, 1.3 mmol) in dichloromethane (10 mL) at 0° C. under argon was addedtriethylamine (0.2 mL, 2.2 mmol), followed bytrimethylsilyltrifluoromethane sulfonate (240 mg, 2.2 mmol). After 1 h,1.0 M sodium hydroxide (4 mL) was added, followed by diethyl ether (20mL). The organic phase was separated, dried over sodium sulfate andconcentrated to an oil, which was purified by column chromatography(PE/EA=10:1) to obtain intermediate DA (290 mg, yield 59%).

Preparation of4-bromo-1-chloro-2-(4-(2-cyclopropoxypropoxy)benzyl)benzene(Intermediate DB)

To a solution of diethyl zinc (1.9 mL, 1.0 M in hexane) indichloromethane (10 mL) at 0° C. under argon was added slowlydiiodomethane (0.15 mL) in dichloromethane (2 mL). After stirring for 30min, 4-bromo-1-chloro-2-(4-(2-(vinyloxy)propoxy)benzyl)benzene (290 mg,0.76 mmol) in dichloromethane (3 mL) was added dropwise. The reactionmixture was warmed to room temperature and stirred overnight, and thenquenched with saturated aqueous ammonium chloride. The aqueous layer wasextracted with ethyl acetate, and the combined organic layers werewashed with saturated aqueous sodium bicarbonate and then with brine,and then dried over sodium sulfate. The residue was concentrated andpurified by preparative TLC to obtain intermediate DB as an oil (200 mg,yield 66%). ¹H NMR (CDCl₃, 400 MHz): δ 7.24-7.31 (m, 3H), 7.10-7.12 (m,2H), 6.87-6.89 (m, 2H), 3.90-4.01 (m, 5H), 3.47-3.48 (m, 1H), 1.31-1.33(m, 3H), 0.64 (m, 2H), 0.50-0.53 (m, 2H).

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxypropoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound DC)

To a solution of4-bromo-1-chloro-2-(4-(2-cyclopropoxypropoxy)benzyl)benzene (180 g, 0.45mol) in anhydrous toluene/tetrahydrofuran (v/v=2:1, 1 mL), n-BuLi (0.22mL, 2.5 M in hexane) was added dropwise at −78° C. The mixture wasstirred for 30 min, and then transferred to a solution of(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one(276 mg, 0.6 mmol) in anhydrous toluene (1 mL) at −78° C. The mixturewas stirred at −78° C. for 2 h until starting material was consumed. Thereaction was quenched with methanesulfonic acid (60 μL in 1.2 mLmethanol), and the mixture was allowed to warm to room temperature andstirred overnight. Then water was added, the organic phase wasseparated, and the water phase was extracted with ethyl acetate. Theorganic phases were combined, washed with saturated sodium bicarbonate,then with water and then with brine, and then dried over anhydroussodium sulfate. The residue was filtered and concentrated to get thecrude product, which then was dissolved in acetonitrile/dichloromethane(2 mL, 1:1). Triethylsilane (0.3 mL, 1.9 mmol) was added, the mixturewas cooled to −40° C. and boron trifluoride diethyl etherate (1.8 μL,1.4 mmol) was added quickly. After addition, the mixture was stirred for2 h at 0° C. The reaction was quenched with saturated aqueous sodiumbicarbonate. The volatiles were removed under reduced pressure, and theresidue was extracted with ethyl acetate and washed with water and thenwith brine, and then dried over anhydrous sodium sulfate. The residuewas filtered, concentrated, and purified by prepared LC-MS to obtaincompound DC (7.2 mg). ¹H NMR (CD₃OD, 400 MHz): δ 7.28-7.37 (m, 3H),7.11-7.13 (m, 2H), 6.83-6.85 (m, 2H), 3.88-4.12 (m, 7H), 3.69-3.73 (m,1H), 3.40-3.53 (m, 4H), 3.28-3.33 (m, 1H), 1.27-1.29 (d, J=8 Hz, 3H),0.48-0.60 (m, 4H); MS ES⁻ (m/z): 523 (M+45)⁻; MS ES⁺ (m/z): 479 (M+1)⁺,496 (M+18)⁺.

Example 32

The synthesis of compound DJ within the invention is outlined in FIG.29, with the details given below.

Preparation of(5-bromo-2-chlorophenyl)(4-(3-bromopropyl)phenyl)methanone (IntermediateDD)

To a stirred suspension of 5-bromo-2-chlorobenzoic acid (2.31 g, 9.80mmol) and oxalyl chloride (1.41 g, 11.11 mmol) in CH₂Cl₂ (30 mL) wasadded 0.05 mL of DMF. Once the vigorous evolution of gas ceased, thereaction was stirred overnight and then the volatiles were removed underreduced pressure. The resulting crude 5-bromo-2-chlorobenzoyl chloridewas dissolved in dichloromethane (30 mL), and the solution was cooled to0˜5° C. Then AlCl₃ (1.31 g, 9.8 mmol) was added in portions, the mixturewas stirred for 30 min, and (3-bromopropyl)benzene (1.50 g, 6.53 mmol)in dichloromethane (4 mL) was added. The reaction solution was warmed toroom temperature and stirred for 4 h. The reaction was quenched bypouring into ice water. The suspension was diluted with water andextracted 3× with CH₂Cl₂. The combined organic extracts were washed 2×with 1N HCl, 1× with water, 2× with 1M NaOH, and 2× with brine, and thendried over Na₂SO₄. After removal of the volatiles, the crude product waspurified by column chromatography (eluent EA:PE=1:20) to obtainintermediate DD (2.4 g) as a light yellow oil. ¹H-NMR (CDCl₃, 400 MHz):δ 7.68˜7.66 (d, J=2H), 7.50˜7.47 (dd, J=1H), 7.42 (d, J=1H), 7.28˜7.19(m, 3H), 3.33 (t, J=6.8 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 2.17˜2.10 (m,2H).

Preparation of 4-bromo-2-(4-(3-bromopropyl)benzyl)-1-chlorobenzene(Intermediate DE)

To a stirred solution of Et₃SiH (1.4 mL, 8.50 mmol) and(5-bromo-2-chlorophenyl)(4-(3-bromopropyl)phenyl)methanone (2.36 g, 5.67mmol) in TFA (10 mL) at 30° C. was added CF₃SO₃H (0.05 mL). Within a fewminutes the temperature of the solution increased causing it to refluxviolently. After stirring for 2.5 h, additional Et₃SiH (0.45 mL, 2.85mmol) was added and the mixture was heated to 50° C. After stirring for4.5 h the reaction was complete, and the volatiles were removed underreduced pressure. The residue was poured into brine and extracted 3×with ethyl acetate. The combined organic layers were washed 3× withwater, 2× with aqueous Na₂CO₃ and 2× with brine, and dried over Na₂SO₄.The solvent was evaporated under reduced pressure, and the residue (2.3g) was used in the next step without further purification.

Preparation of 3-(4-(5-bromo-2-chlorobenzyl)phenyl)propan-1-ol(Intermediate DF)

To a solution of 4-bromo-2-(4-(3-bromopropyl)benzyl-1-chlorobenzene (2.3g, 5.7 mmol) in DMF (12 mL) was added sodium acetate (0.7 g, 8.5 mmol).The solution was heated to 90° C. and stirred overnight. Water (50 mL)and ethyl acetate (100 mL) were added. The organic layer was separated,washed with saturated NH₄Cl, then with water and then with brine, anddried over Na₂SO₄. The solvent was evaporated under reduced pressure toobtain a yellow oil (2.3 g), which was dissolved in a mixture ofTHF:MeOH:H₂O (v/v/v=3:5:2, 10 mL). Sodium hydroxide (0.3 g, 7.23 mmol)was added, and the mixture was stirred for 1.5 h. The reaction wasquenched with 20 mL of water, volatiles were removed under reducedpressure, and the residue was extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with 2N dilute hydrochloride(2×20 mL), then with water and then with brine, and then dried oversodium sulfate. After concentration, the residue was purified by columnchromatography (eluent EA:PE=5:1) to obtain intermediate DF (1.6 g) as ayellow oil, ¹H-NMR (CDCl₃, 400 MHz): δ 7.32˜7.25 (m, 3H), 7.17 (d, 2H),7.12 (d, 2H), 4.05 (s, 1H), 3.70 (t, J=6.8 Hz, 2H), 2.72 (t, J=7.6 Hz,2H), 1.95˜1.88 (m, 2H).

Preparation of 4-bromo-1-chloro-2-(4-(3-(vinyloxy)propyl)benzyl)benzene(Intermediate DG)

To a solution of 3-(4-(5-bromo-2-chlorobenzyl)phenyl)propan-1-ol (0.88g, 2.59 mmol), [IrCl(cod)]₂ (17 mg, 0.026 mmol) and sodium carbonate(0.17 g, 1.56 mmol) in toluene (5 mL) was added vinyl acetate (0.48 mL,5.18 mmol) under argon. The reaction mixture was heated to 100° C. andstirred for 5 h. The solution was allowed to cool to room temperature,and then diluted with 60 mL of ethyl acetate. The mixture was washedwith water (20 mL) and then with brine (20 mL), and dried over sodiumsulfate. The residue was concentrated and purified by columnchromatography (eluent EA:PE:Et₃N=1:30:0.01) to provide 0.75 g of whitesolid. ¹H NMR (CDCl₃, 400 MHz): δ 7.29˜7.24 (m, 3H), 7.15 (d, 2H), 7.11(d, J=2H), 6.50 (dd, J=14.4 and 6.8 Hz, 1H), 4.18 (dd, J=14.4 and 2.0Hz, 1H), 4.04 (s, 2H), 4.00 (dd, J=6.8 and 2.0 Hz, 1H), 3.71 (t, J=6.4Hz, 2H), 2.70 (t, J=7.2 Hz, 2H), 2.06˜1.96 (m, 2H).

Preparation of4-bromo-1-chloro-2-(4-(3-cyclopropoxypropyl)benzyl)benzene (IntermediateDH)

To a stirred mixture of4-bromo-1-chloro-2-(4-3-(vinyloxy)propyl)benzyl)benzene (0.75 g, 2.04mini) and Et₂Zn (5.11 mL, 5.11 mmol, 1.0 M in hexane) in dry ethyl ether(10 mL) was added diiodomethane (0.41 mL, 5.11 mmol) dropwise during 20min at room temperature under argon. After stirring overnight, thereaction mixture was poured slowly into ice cold dilute hydrochloridesolution with stirring. The mixture was extracted with ethyl acetate(3×20 mL). The combined organic layers were washed with water (20 mL)and then with brine (20 mL), and then dried over sodium sulfate. Theresidue was concentrated and purified by preparative TLC (eluentEA:PE=1:40) to obtain intermediate DH (0.64 g) as a light yellow oil. ¹HNMR (CDCl₃, 400 MHz): δ 7.32˜7.25 (m, 3H), 7.15 (d, J=2H), 7.11 (d, 2H),4.05 (s, 2H), 3.53 (t, J=6.4 Hz, 2H), 3.31˜3.26 (m, 1H), 2.68 (t, J=7.2Hz, 2H), 1.93˜1.86 (m, 2H), 0.61˜0.45 (m, 4H).

Preparation of(3R,4S,5S,6R)-2-(4-chloro-3-(4-(3-cyclopropoxypropyl)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol(Intermediate DI)

To a solution of4-bromo-1-chloro-2-(4-(3-cyclopropoxypropyl)benzyl)benzene (0.64 g, 1.69mmol) in anhydrous toluene/THF (6 mL, v/v=2:1) was added dropwise n-BuLi(2.5 M in hexane, 0.81 mL) at −65° C., and the mixture was stirred for30 min at −65° C. Then a −65° C. solution of(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one(0.86 g, 1.85 mmol) toluene (6 mL) was added dropwise over 15 min. Themixture was stirred at −65° C. for 3.5 h until starting material wasconsumed. The reaction was quenched with methanesulfonic acid (0.23 mL,3.58 mmol) in methanol (6 mL), and the mixture was allowed to warm toroom temperature and stirred overnight. The reaction was quenched withsaturated sodium bicarbonate, the organic phase was separated and theaqueous phase was extracted with ethyl acetate. The combined organicphases were washed with saturated bicarbonate, then with water, and thenwith brine, and dried over sodium sulfate. Removal of the volatilesafforded a residue (0.73 g), which was used in the next step withoutfurther purification.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(3-cyclopropoxypropyl)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Compound DJ)

To a −15° C. solution of crude product from the previous step (0.60 g,1.22 mmol) in anhydrous acetonitrile/dichloromethane (6 mL, 1:1) wasadded triethylsilane (0.78 mL, 4.87 mmol), Then BF₃.Et₂O (0.46 mL, 3.65mmol) was added dropwise, and the mixture was stirred for 3 h at −15° C.The reaction was quenched with saturated aqueous bicarbonate and thevolatiles were removed under reduced pressure. The residue was extractedwith ethyl acetate, washed with water, then with brine, and dried oversodium sulfate. The sample was concentrated and purified by preparativeHPLC-MS to give 0.29 g of white solid. ¹H NMR (CD₃OD, 400 MHz): δ7.38˜7.29 (m, 3H), 7.12 (d, J=2H), 7.09 (d, 2H), 4.11 (d, J=9.2 Hz, 1H),4.13˜4.03 (dd, J=24.4 and 14.8 Hz, 2H), 3.91˜3.88 (m, 1H), 3.73˜3.68 (m,1H), 3.50 (t, J=6.4 Hz, 2H), 3.47˜3.40 (m, 3H), 3.30˜3.27 (m, 2H), 2.62(t, J=7.2 Hz, 2H), 1.87˜1.80 (m, 2H), 0.54˜0.44 (m, 4H); MS ESI (m/z):463 [M+H]⁺, calc. 462.

Example 33

The synthesis of complex DM within the invention is outlined in FIG. 30,with the details given below.

Preparation of 2-cyclopropoxyethanol (Intermediate BO)

To a suspension of Mg powder (86.7 g, 3.6 mol) and I₂ (catalytic) inanhydrous THF (0.7 L) was added slowly 1,2-dibromoethane (460 g, 2.4mol) in anhydrous THF (2 L) at a rate that maintained the reactiontemperature between 40-55° C. A solution of2-(2-bromoethyl)-1,3-dioxolane (100 g, 0.56 mol) in anhydrous THF (750mL) was added dropwise, and the reaction mixture was kept at 40-55° C.for 16 h. The reaction was quenched by addition of an aqueous solutionof ammonium chloride. The mixture was extracted with methylene chloride.The organic layer was dried over sodium sulfate, and concentrated togive intermediate BO (27 g) as yellow oil, which was used in the nextstep without further purification.

Preparation of 2-cyclopropoxyethyl 4-methylbenzenesulfonate(Intermediate BP)

To a stirred solution of sodium hydroxide (32 g, 0.8 mol) in water (180mL) and THF (180 mL) was added crude 2-cyclopropoxyethanol from theprevious step (27 g, 0.26 mol) at −5 to 0° C. A solution ofp-toluenesulfonyl chloride (52 g, 0.27 mol) in THF (360 mL) was addeddropwise, and the reaction mixture was kept at −5 to 0° C. for 16 h. Thereaction mixture was then incubated at room temperature for 30 min, theorganic layer was separated and the aqueous layer was extracted withethyl acetate (2×1.0 L). The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated to get the crude intermediateBP as a yellow oil (53.3 g), which was used for the preparation ofintermediate DK below without further purification.

Preparation of 4-(5-bromo-2-chlorobenzyl)phenol (Intermediate II)

To a stirred solution of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene(intermediate B) (747 g, 2.31 mol) in dichloromethane was added slowlyboron tribromide (1.15 kg, 4.62 mol) at −78° C. The reaction mixture wasallowed to warm to room temperature. When the reaction was complete asmeasured by TLC, the reaction was quenched with water. The mixture wasextracted with dichloromethane. The organic layer was washed with anaqueous solution of saturated sodium bicarbonate, then with water, andthen with brine, and dried over Na₂SO₄. The residue was concentrated andthen recrystallized in petroleum ether to obtain intermediate H as awhite solid (460 g, yield 68%). ¹H NMR (CDCl₃, 400 MHz): δ 7.23˜7.29 (m,3H), 7.08 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 5.01 (s, 1H), 4.00(s, 2H).

Preparation of4-bromo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene (IntermediateDK)

A mixture of 4-(5-bromo-2-chlorobenzyl)phenol (56.7 g, 210 mmol) andCs₂CO₃ (135 g, 420 mmol) in DMF (350 mL) was stirred at room temperaturefor 30 min, and then 2-cyclopropoxyethyl 4-methylbenzenesulfonate (crudeintermediate BP from the second preceeding step above) (53.3 g, 210mmol) was added. The reaction mixture was stirred at room temperatureovernight, and then diluted with water (3 L) and extracted with EtOAc.The organic layer was washed with water, then with brine, and dried overNa₂SO₄. The residue was concentrated and then purified by flash columnchromatography on silica gel (eluent PE:EA=10:1) to give intermediate DKas a liquid (51 g, yield 64%). ¹H NMR (CDCl₃, 400 MHz): δ 7.22˜7.29 (m,3H), 7.08 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.10 (t, J=4.8 Hz,2H), 3.86 (t, J=4.8 Hz, 2H), 3.38-3.32 (m, 1H), 0.62-0.66 (m, 2H),0.49-0.52 (m, 2H).

Preparation of(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol(Intermediate DL)

To a stirred solution of4-bromo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene (213 g) inanhydrous THF/toluene (1:2 v/v, 1.7 L) under argon was added n-BuLi (2.5M in hexane, 245.9 mL) dropwise at −60±5° C. The mixture was stirred for30 min, and then transferred to a stirred solution of(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one(310.5 g) in toluene (1.6 L) at −60±5° C. The reaction mixture wascontinuously stirred at −60±5° C. for 1 before quenching with an aqueoussolution of saturated ammonium chloride (1.5 L). The mixture was allowedto warm to room temperature and stirred for 1 h. The organic layer wasseparated and the water layer was extracted with ethyl acetate (3×500mL). The combined organic layers were washed with brine (1 L), driedover Na₂SO₄, and concentrated. The residue was dissolved in methanol(450 mL), and methanesulfonic acid (9.2 mL) was added at 0° C. Thesolution was allowed to warm to room temperature and stirred for 2.0 h.The reaction was quenched with an aqueous solution of sodium bicarbonate(50 g) in water (500 mL) and then additional water (900 mL) was added.The mixture was extracted with ethyl acetate (3×1.0 L). The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated. The crude product was used in the next step withoutfurther purification.

Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,bis(L-proline) complex (Complex DM)

To a stirred solution of crude(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triolfrom the previous step in CH₂Cl₂/CH₃CN (1:1, 1.3 L) at −5° C. was addedtriethylsilane (28.2 mL, 563 mmol), followed by BF₃.Et₂O (52.3 mL, 418.9mmol). The reaction was stirred for 16 h while the temperature wasallowed to warm gradually to room temperature. The reaction was quenchedby addition of an aqueous solution of saturated sodium bicarbonate to pH8.0. The organic volatiles were removed under vacuum. The residue waspartitioned between ethyl acetate (2.25 L) and water (2.25 L). Theorganic layer was separated, washed with brine, dried over Na₂SO₄ andconcentrated to give the crude product (230 g, purity 82.3%). To thecrude product was added L-proline (113.7 g) in EtOH/H₂O (15:1 v/v, 2.09L), and the mixture was stirred at 80° C. for 1 h until it became aclear solution. Hexane (3.0 L) was added dropwise over 50 min, while thetemperature was maintained at about 60° C. The reaction mixture wasstirred overnight at room temperature. The solid was filtered and washedwith EtOH/H₂O (15:1 v/v, 2×300 mL), hexane (2×900 mL), and dried at 45°C. under vacuum for 10 h to give pure complex DM as a white solid (209g; HPLC purity 99.2% (UV)). ¹H NMR (CD₃OD, 400 MHz): δ 7.25˜7.34 (m,3H), 7.11 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 4.03-4.11 (m, 5H),3.96-4.00 (m, 2H), 3.83-3.90 (m, 3H), 3.68-3.72 (m, 1H), 3.36-3.46 (m,6H), 3.21-3.30 (m, 3H), 2.26-2.34 (m, 2H), 2.08-2.17 (m, 2H), 1.94-2.02(m, 4H), 0.56-0.57 (m, 2H), 0.52-0.53 (m, 2H).

Crystalline complex DM was analyzed by X-ray powder diffraction usingCuK_(α1) radiation. The diffraction pattern is shown in FIG. 31 andsummarized in Table 1 (only peaks up to 30° in 2θ are listed). Themelting point of complex DM was determined by differential scanningcalorimetry (DSC) as 151±1° C. (evaluated as onset-temperature; heatingfrom 50° C. to 200° C. at 10° C./min). The DSC spectrum is shown in FIG.32.

TABLE 1 Position [°2θ] d-spacing [Å] Relative Intensity[%] 4.08 21.62100.0 6.04 14.63 8.1 7.50 11.77 5.3 9.88 8.95 2.3 12.31 7.18 9.9 14.226.22 6.7 16.44 5.39 16.3 17.18 5.16 30.9 17.89 4.96 9.6 18.47 4.80 4.118.97 4.67 4.0 19.85 4.47 7.7 20.60 4.31 14.1 21.10 4.21 14.8 21.88 4.065.9 22.72 3.91 2.7 23.38 3.80 2.8 24.49 3.63 2.1 25.17 3.54 2.5 26.433.37 1.4 26.97 3.30 3.1 28.36 3.14 2.2 29.23 3.05 1.6

Example 34

The SGLT inhibitory effects of the compounds of the present inventionwere demonstrated by the following procedures.

Preparation of Human SGLT2 Expression Vector

A full-length cDNA clone expressing human SGLT2 (GenScript Corporation)was subcloned into Hind III and Not I sites of pEAK15 expression vector.Clones harboring the cDNA inserts were identified by restrictionanalysis.

Preparation of a Cell Line Stably Expressing Human SGLT2

Plasmid containing human SGLT2 was linearized with Nsi I and purified byagarose gel electrophoresis. Using Lipofectamine 2000 TransfectionReagent (Invitrogen Corporation), DNA was transfected into HEK293.ETNcells and cultured in Dulbecco's Modified Eagle Medium (DMEM) containing10% fetal bovine serum (FBS) at 37° C. under 5% CO₂ for 24 h.Transfectants were selected in the same growth medium supplemented withpuromycin (invitrogen Corporation) for two weeks. Puromycin-resistantcells were recovered and seeded on a fresh 96-well plate (single cellper well) and cultured in the presence of puromycin until cells becameconfluent. Puromycin-resistant clones were evaluated for SGLT2 activityin the methyl-α-D-[U-¹⁴C]glucopyranoside uptake assay described below.The clone that exhibited the highest signal-to-background ratio was usedfor the methyl-α-D-[U-¹⁴C]glucopyranoside uptake assay.

Preparation of Human SGLT1 Expressing Cells

Full-length human SGLT1 cDNA on pDream2.1 expression vector was obtainedfrom GenScript Corporation and propagated in Escherichia coli strainDH5α using Luria-Bertani (LB) medium containing ampicillin. Plasmid DNAwas isolated using the QIAGEN Plasmid Midi Kit (QIAGEN Inc.). HumanSGLT1 expression plasmid DNA was transfected into COS-7 cells (AmericanType Culture Collection) using Lipofectamine 2000 Transfection Reagentaccording to a manufacturer suggested protocol. Transfected cells werestored in DMEM containing 10% dimethyl sulfoxide (DMSO) at −80° C.

Methyl-α-D-[U-¹⁴C]glucopyranoside Uptake Assay

Cells expressing SGLT1 or SGLT2 were seeded on 96-well ScintiPlatescintillating plates (PerkinElmer, Inc.) in DMEM containing 10% FBS(1×10⁵ cells per well in 100 μl medium) incubated at 37° C. under 5% CO₂for 48 h prior to the assay. Cells were washed twice with 150 μl ofeither sodium buffer (137 in M NaCl, 5.4 mM KCl, 2.8 in M CaCl₂, 1.2 mMMgCl₂, 10 mMtris(hydroxymethyl)aminomethane/N-2-hydroxyethylpiperazine-N′-ethanesulfonicacid [Tris/Hepes], pH 7.2) or sodium-free buffer (137 mMN-methyl-glucamine, 5.4 mM KCl, 2.8 mM CaCl₂, 1.2 mM MgCl₂, 10 mMTris/Hepes, pH 7.2). Test compound in 50 μl each of sodium orsodium-free buffer containing 40 μCi/mlmethyl-α-D-[U-¹⁴C]glucopyranoside (Amersham Biosciences/GE Healthcare),either with (symbols in parentheses) or without (symbols withoutparentheses) 25% human serum, was added per well of a 96-well plate andincubated at 37° C. with shaking for either 2 h (SGLT1 assay) or 1.5 h(SGLT2 assay). Cells were washed twice with 150 μl of wash buffer (137mM N-methylglucamine, 10 mM Tris/Hepes, pH 7.2) andmethyl-α-D-[U-¹⁴C]glucopyranoside uptake was quantitated using aTopCount scintillation counter, (PerkinElmer, Inc.). Sodium-dependentglucopyranoside uptake was measured by subtracting the values obtainedwith sodium-free buffer from those obtained using sodium buffer (averageof triplicate determinations).

TABLE 2 IC₅₀* Compound SGLT2 SGLT1 M + ++ P (+) (++) R (+) (++) T (+)(+++) X (+) (++) Z (+) (+++) AD (+) (++) AV (+) (+++) BN (+) (+++) BQ(+) (++) BT (+) (++) BW (+) (+++) BZ (+) (+++) CC + ++ CF + ++ CH (+)(++) CK (+) (++) CM (+) (+++) CP (+) (+++) CT (+) (+++) CX (+) (+++) DC(+) (++) DJ (+) (++) *Key: + <1 μM ++ 1 μM to 10 μM +++ >10 μm ( )indicates incubation with 25% human serum

What is claimed is:
 1. A compound of Formula IA:

wherein V is oxygen; W is C₁-C₆ alkylene; X is oxygen; Y is a memberselected from the group consisting of C₁-C₆ haloalkyl, alkenyl, C₂-C₆alkynyl, C₃-C₁₀ cycloalkyl and (C₁-C₄ alkyloxy)C₁-C₃ alkyl; and R′ ischloro.
 2. A compound of claim 1, wherein Y is C₃-C₆ cycloalkyl.
 3. Acompound of claim 1, selected from the group consisting of:(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(3-(4-(2-(allyloxy)ethoxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(prop-2-ynyloxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(1-(prop-2-ynyloxy)propan-2-yloxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(cyclopentyloxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2,2,2-trifluoroethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2,4-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2-fluoroethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2,2-difluoroethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclobutoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;and(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxypropoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.4. A compound represented by the formula:


5. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of any of claims 1 to
 3. 6. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and thecompound of claim
 4. 7. A method of treating type 2 diabetes, saidmethod comprising administering to a subject in need thereof atherapeutically effective amount of a compound of claim 4 or acomposition of claim 6.